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© 1999 American Heart Association, Inc.
Cellular Biology |
Upregulation of Na+/Ca2+ Exchanger Expression and Function in an Arrhythmogenic Rabbit Model of Heart Failure
From the University of Illinois at Chicago (S.M.P.), Section of Cardiology, Chicago, and Loyola University Chicago, Department of Physiology and Cardiovascular Institute (M.Q., W.Y., A.M.S., D.M.B.), Maywood, Ill.
Correspondence to Steven M. Pogwizd, MD, Section of Cardiology, University of Illinois at Chicago, 840 S Wood Street, M/C 787, Chicago, IL 60612-7323.
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Abstract |
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Abstract—Three-dimensional cardiac mapping in rabbits with nonischemic cardiomyopathy has shown that ventricular arrhythmias initiate by a nonreentrant mechanism that may be due to triggered activity from delayed afterdepolarizations. Delayed afterdepolarizations are thought to be due to spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR) and consequent activation of an inward Na+/Ca2+ exchange (NaCaX) current. The goal of this study was to determine whether there is enhanced NaCaX gene expression and functional activity that may contribute to nonreentrant activation. Heart failure (HF) was induced in rabbits by combined aortic insufficiency and aortic constriction. HF rabbits had left ventricular enlargement (left ventricular end-diastolic dimension increased from 1.43±0.03 to 1.97±0.05 cm) and severely depressed function (fractional shortening reduced from 37% to 26%, P<0.02). Heart-to-body weight was increased by 79% in HF. Western blots showed a 93% increase in NaCaX protein in HF (P<0.04). NaCaX mRNA (7-kb transcript) was increased by 104% relative to the 18S rRNA in HF. A 14-kb NaCaX transcript was also seen in the HF rabbits, raising total NaCaX mRNA to 2.7-fold compared with controls. The amplitude of caffeine-induced contractures, used to assess SR Ca2+ load, was not significantly different in HF. Relaxation and [Ca2+]i decline during caffeine-induced contractures is attributable to Ca2+ transport by NaCaX and was 61% and 45% faster in HF (P<0.05), respectively. NaCaX current measured under controlled voltage clamp conditions was also 2-fold higher in HF cells. SR Ca2+-ATPase mRNA and protein levels and Ca2+ current density were not significantly altered in HF. Twitch amplitudes from HF myocytes were 26% smaller compared with control (P<0.02), but twitch relaxation and [Ca2+]i decline (due largely to SR Ca2+-ATPase) were not altered. Thus myocytes and myocardium from HF rabbits exhibit enhanced NaCaX expression and function. The enhanced NaCaX activity may contribute to depressed contractions, increased transient inward current (for a given SR Ca2+ release), delayed afterdepolarizations, and nonreentrant initiation of ventricular tachycardia in this arrhythmogenic model of HF.
Key Words: heart failure • Na+/Ca2+ exchange • ventricular tachycardia • delayed afterdepolarization • Ca2+
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sudden death in patients with congestive heart failure (HF) is commonly due to lethal ventricular arrhythmias, including ventricular tachycardia (VT) and ventricular fibrillation.1 2 However, very little is known about the electrophysiologic and molecular mechanisms underlying arrhythmogenesis in HF. An understanding will require 1) development of arrhythmogenic animal models of HF, 2) delineation of the arrhythmic mechanisms in these animal models, 3) validation of these mechanisms by studies in the human heart, and 4) assessment of the function and expression of the channels and carrier proteins that may underlie these arrhythmic mechanisms.
There are a considerable number of experimental animal models of HF,3 but very few are arrhythmogenic. An arrhythmogenic experimental model of nonischemic cardiomyopathy has recently been developed in rabbits, combining aortic insufficiency and aortic constriction.4 5 These HF rabbits develop severe depression of left ventricular (LV) function, pathologic alterations similar to that in patients with nonischemic cardiomyopathy, and spontaneously-occurring VT.3 Using 3D cardiac mapping, Pogwizd5 has demonstrated that the spontaneously-occurring VT in these HF rabbits initiates by a nonreentrant mechanism. Recent 3D mapping studies in failing human hearts at the time of heart transplantation in patients with idiopathic dilated cardiomyopathy have demonstrated that spontaneous and induced VT in these patients also initiates by a focal nonreentrant mechanism.6
The nature of this nonreentrant mechanism in the myopathic heart is unknown. Vermeulen et al7 have demonstrated that failing myocardium from rabbits with aortic insufficiency and aortic stenosis demonstrate delayed afterdepolarizations (DADs) when exposed to catecholamines and rapid pacing. These findings suggest that DADs, due to a transient inward current (Iti) mediated by Na+/Ca2+ exchange (NaCaX) or a nonspecific cationic current,8 9 may underlie the nonreentrant mechanism in the setting of nonischemic cardiomyopathy.
The goal of the present study was to test the hypothesis that this arrhythmogenic model of HF demonstrates upregulation of NaCaX (as in failing human heart10 11 ) and enhanced functional NaCaX activity and current, which could underlie development of Iti. We therefore quantitated the levels of NaCaX mRNA and protein in myocardial tissue from failing and control rabbits by Northern blotting and immunoblotting. Decreased expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2) has been noted in some experimental models of HF12 and in the failing human heart.13 14 15 Those changes could also contribute to arrhythmias by increasing levels of cytoplasmic Ca2+. Thus we also assessed the levels of SERCA2 mRNA and protein. Studies were also performed in isolated myocytes from control and HF rabbits to assess the functional activity of NaCaX and SERCA2 (during twitch and caffeine-induced contractures [CafC]) and the levels of NaCaX current (INa/Ca) and Ca2+ current (ICa).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal Preparations and Induction of HF
Studies were performed on healthy adult New Zealand White rabbits of either sex (2.9 to 3.5 kg; Doe Valley Farms, Inc, Bentonville, Ark). HF was produced by combined aortic insufficiency (AI) and aortic constriction. Induction of AI was performed by inserting a beveled catheter via the left carotid artery and repeatedly pushing it through the aortic valve to increase pulse pressure by at least 50%, as previously described.5 The severity of AI was assessed by 2D echocardiography with color flow mapping.16 After 14 to 28 days, a left thoracotomy was performed, allowing aortic constriction (to 2.42 mm) just distal to the left subclavian artery.5 The protocol was approved by the Animal Studies Committees of Washington University and the University of Illinois at Chicago.
At baseline and at approximately 3- to 6-month intervals, each rabbit underwent echocardiographic examination as previously described.5 M-mode echocardiographic measurements of left ventricular end-diastolic (LVEDD) and end-systolic (LVESD) dimensions were obtained.17 Fractional shortening (FS) was calculated as: FS(%)=(LVEDD-LVESD)/LVEDD.
At baseline and at an average of once every 2 to 4 weeks after aortic constriction, Holter monitor recordings were obtained for 24-hour periods from the rabbits while they were conscious, as previously described.5
RNA Isolation and Northern Blotting
RNA was isolated from LV tissue,18
size-fractionated by agarose gel electrophoresis, and then transferred
to nylon membranes.19 Detection of cardiac NaCaX mRNA used
1.3 kb cDNA of guinea pig cardiac NaCaX (from Dr K.D. Philipson,
University of California, Los Angeles). Detection of SERCA2 used 2.3 kb
cDNA from rat cardiac SERCA2 (from Dr W. Dillmann, University of
California, San Diego). Signal intensity was quantified by
autoradiography (-80°C) and laser densitometry and
was normalized to that of 18S rRNA and of
glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
mRNA.20
Immunoblotting
For the quantitative analysis of NaCaX and SERCA2
protein, LV tissue (200 to 300 mg) was homogenized in 9
volumes of extraction buffer and diluted into electrophoresis sample
buffer for separation on 7.5% SDS-polyacrylamide
gels.12 After transfer to nitrocellulose21
and blocking with nonfat milk (5% wt/vol), blots were incubated with
rabbit anti-dog NaCaX antiserum (from Dr K.D. Philipson, University of
California, Los Angeles) or with rabbit anti-rat SERCA2 antiserum (from
Drs R. Hartong and W. Dillmann, University of California, San Diego).
Primary antibody binding was detected with an ECL Western blotting kit
(Amersham) and quantified by laser densitometry.
Myocyte Isolation
Left ventricular myocytes were isolated via
Langenddorf perfusion with 0.5 mg/mL collagenase as
described,22 except that back flow across the incompetent
aortic valve in HF rabbits was blocked by a balloon-tipped catheter
inserted across the aortic valve and inflated in the LV outflow tract.
Also, additional incubations with 0.4 mg/mL collagenase
plus 0.02 mg/mL pronase were done at 37°C for up to 12 minutes. Cells
were studied at 23°C or 37°C in superfusion chambers on glass
coverslip bases pretreated with laminin.
Contractions and Ca2+ Transients
Along with cell shortening,
[Ca2+]i was measured
using indo 1 fluorescence (excited at 365 nm and measured at
405 and 485 nm, Kd=441 nmol/L) as
described.23 Normal Tyrode’s (NT) solution contained
(in mmol/L): NaCl 140, KCl 4, MgCl2 1,
CaCl2 2, glucose 10, and HEPES 5, pH 7.4 at
23°C. After steady-state twitches (0.5 Hz), stimulation was stopped
and NT+10 mmol/L caffeine solution (NTCaff) was rapidly applied
for 10 seconds (causing SR Ca2+ release and
extrusion via NaCaX22 23 ).
Whole-Cell Voltage Clamp
Ion currents were measured with the whole cell ruptured-patch
technique (pipette tip resistance=0.8 to 1.2 M
) with membrane
capacitance measured by 5 mV voltage steps from -80 mV.
INa/Ca was measured as described by Hobai
et al.24 Pipettes were filled with (in mmol/L)
45 CsCl, 55 Cs methanesulfonic acid, 10 ATP-tris, 0.3
GTP-tris, 20 HEPES, 10.8 MgCl2 (1 mmol/L
free Mg), 5 1,2-bis(2aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, 5
DiBr-1,2-bis(2aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, 2.21
CaCl2 (100 nmol/L free Ca), and 14 NaCl (pH 7.3
with CsOH). To isolate INa/Ca, the NT
(37°C) was modified (6 CsCl replaced KCl, and 10 µmol/L
strophanthidin, 30 mmol/L BDM and sometimes 10 µmol/L
nifedipine were added). Ni (5 mmol/L) was added to
block ICa and
INa/Ca.
Data Analysis
All results were expressed as means±SE and unpaired
t tests were used to compare 2 groups (significance at
P<0.05).
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Development of Hypertrophy and Failure
HF was induced in 13 rabbits. Severe aortic insufficiency, confirmed by 2D color flow Doppler echocardiography, was first produced. Two to 6 weeks later, aortic constriction was performed. Over the subsequent 1 to 24 months, the rabbits developed progressive cardiac enlargement and decreased left ventricular systolic function. LVEDD increased by 40% (P<0.001), and LVESD increased by 68% (P<0.0001, Table 1
). Mean
fractional shortening decreased from 36±2% to 23±1%
(P<0.0001). The 6 age-matched control rabbits demonstrated
LVEDD, LVESD, and fractional shortening that were comparable with
baseline values for the rabbits that underwent induction of HF (Table 1). There were significant increases in heart weight and
heart-to-body weight ratio (77% and 79%, respectively),
whereas body weight was not different between control and HF rabbits
(Table 1). There was also a corresponding significant increase
in resting myocyte length (31%) and width (45%) in cells isolated
from control and HF rabbits (Table 1) resulting in an 89%
increase in the lengthxwidth product.
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Spontaneously Occurring Ventricular Arrhythmias
Holter monitoring in the conscious state was performed in 11
rabbits at baseline and, on average, every 1 to 2 months after the
induction of HF in 10 of the 11 rabbits. At baseline, none of the
rabbits exhibited any ventricular arrhythmias.
However, over the course of the 1 to 24 months after the induction of
HF, all of the HF rabbits exhibited spontaneously-occurring
ventricular arrhythmias, with up to 13 339
premature ventricular complexes, 402 couplets, and 32 runs
of nonsustained VT over the course of 24 hours. Nine of the 10 HF
rabbits demonstrated nonsustained VT during serial Holter monitoring.
The longest run of VT was 31 beats and the fastest was a 15 beat run of
VT at a rate of 360 beats per minute (Figure 1).
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Arrhythmogenic Effects of Isoproterenol
To determine whether HF myocytes also exhibit spontaneous activity
(as in the whole heart in vivo), the appearance of aftercontractions in
isolated myocytes was also studied. Myocytes were field-stimulated at
increasing frequency (0.2 to 1.8 Hz) in the absence and presence of
10 µmol/L isoproterenol. After the 20th
stimulated twitch, there was a 10-second interval with no stimulation
to observe for the presence of aftercontractions. At baseline (without
isoproterenol), no aftercontractions occurred in either control or HF
myocytes (Figure 2). After the addition
of 10 µmol/L isoproterenol, aftercontractions were induced in 4
of 5 HF myocytes but in 0 out of 5 control myocytes studied with this
protocol. Thus HF myocytes exposed to ß-adrenergic agonist
demonstrate spontaneous SR Ca2+ release and the
induction of aftercontractions.
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NaCaX and SERCA2 mRNA and Protein Levels
Figure 3 shows Northern blot
analysis of NaCaX mRNA in LV myocardium from
control and HF rabbits. All control and HF rabbits demonstrated a 7-kb
hybridization band, corresponding to the expected position for the
NaCaX. Four of the 8 HF rabbits also demonstrated a high molecular
weight transcript at ~14 kb that was not evident in any of the
controls. However, on prolonged exposure, the control rabbit with the
highest NaCaX mRNA expression showed very low levels of the 14-kb
transcript. Expression of total NaCaX mRNA, normalized to 18S rRNA, was
increased 2.7-fold in the HF rabbits compared with controls
(P<0.01). If only the 7-kb transcript is considered, there
was still a 2.04-fold increase in NaCaX mRNA expression in the HF group
(P<0.05, see Figure 9). Similar values were obtained
when NaCaX mRNA expression was normalized to GAPDH mRNA (eg, 2.9-fold
increase in HF over controls for 7+14 kb).
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Western blots revealed a single band for NaCaX at 120kDa for both
control and HF rabbits. Quantification indicated a 93% increase of
NaCaX protein expression, consistent with the mRNA data (see
Figure 9
).
Quantification of the levels of SERCA2 mRNA in LV was performed by Northern blot analysis using a 2.3-kb cDNA fragment specific for rat cardiac SERCA2. All control and HF rabbits exhibited a single hybridization band at 4.2 kb. SERCA2 expression of HF rabbits normalized to 18S rRNA or to GAPDH was not significantly different from that of control rabbits. (P=not significant).
Figure 4 shows a Western blot for SERCA2,
revealing a single band at 110 kDa for both control and HF rabbits.
When normalized to the mean level of the control rabbits, the SERCA2
protein levels of the HF rabbits was not significantly different (see
Figure 10). However, as shown in Figure 4, the level of
SERCA2 protein did vary among the HF rabbits. Of note, the lowest level
of SERCA2 protein in the HF rabbits (lanes 1 and 3 of HF) was evident
in the 2 rabbits that had the most marked degree of LV enlargement and
the most severe LV dysfunction. There was no significant relationship
between the levels of NaCaX and SERCA2 protein levels.
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There was good correlation between NaCaX mRNA and protein expression,
especially among the HF group (Figure 5A). We also examined the relationship of
NaCaX (and SERCA) expression to LV systolic function in
individual whole hearts. Figure 5B shows that the level of NaCaX
mRNA and LV fractional shortening (FS) were inversely correlated
(P=0.01). A similar relationship between NaCaX protein and
FS was seen, but it did not attain statistical significance
(P=0.067). There was no significant relationship between FS
and SERCA2 mRNA (Figure 5C) or protein (data not shown).
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Biochemical measurements (above) and isolated myocyte studies (below) were performed in 2 different groups of rabbits. However, in each case, HF rabbits demonstrated comparable levels of LV dilatation, depression of LV systolic function, and incidence of spontaneously-occurring ventricular arrhythmias (measured in both groups). In this regard, they were also comparable with the HF rabbits studied by 3D cardiac mapping.5 NaCaX and SERCA2 expression was assessed in left ventricular homogenates, rather than isolated myocytes. Because SERCA2 and NaCaX are so concentrated in ventricular myocytes, contamination from nonmyocytes in the homogenate were considered inconsequential. In previous studies in hypertrophied rat heart, changes in SERCA2 expression were comparable whether measured in left ventricular homogenate or isolated myocytes.12
Relaxation and [Ca2+]i Decline in
Isolated Cardiac Myocytes
The rate of myocyte relaxation and
[Ca2+]i decline during
sustained application of 10 mmol/L caffeine has been shown to
depend mainly on Ca2+ extrusion by NaCaX in
rabbit ventricular myocytes.22 23 This is
because net SR Ca2+ reuptake is prevented by
caffeine, such that NaCaX only competes with the much slower
sarcolemmal Ca2+-ATPase and mitochondrial
uniporter. Thus relaxation and
[Ca2+]i decline during
CafC provide functional data in the intact cell concerning
Ca2+ transport by NaCaX.
Figure 6C shows CafC in control and HF
myocytes and the normalized relaxation (Figure 6D) is much
faster in HF. Mean data (Table 2) show
that the half-time (t1/2) of relaxation was 546±70 ms
in control and 340±40 ms in HF. Considering relaxation rate to be
inversely proportional to t1/2, this constitutes a
61% increase in NaCaX-dependent relaxation in HF. Figure 7C shows comparable data for
[Ca2+]i during a CafC. In
this case, [Ca2+]i
decline was approximately twice as fast in HF as in control. On
average, [Ca2+]i decline
rate during CafC was 45% faster in HF than control (Table 2).
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Twitch relaxation in normal rabbit ventricular myocytes is
dominated by the SERCA2 but only by a factor of 2 to 3 over the
NaCaX.22 23 Thus the time course of relaxation and
[Ca2+]i decline of
twitches should provide functional information about the SERCA2 in
control versus HF. Figures 6B and 7B show normalized
twitch relaxation and
[Ca2+]i decline in
control and HF. The t1/2 values were not significantly
different between these groups (Table 2). Superficially, this
could be construed as evidence of unchanged SERCA2 function. However,
some additional quantitative analysis may be warranted.
The issue here is that the SERCA2 and NaCaX are competing during the
twitch. Thus, if NaCaX is upregulated and SERCA2 is unchanged (as the
above data indicate), we would expect twitch relaxation to be
accelerated in HF. If we consider simply that relaxation is attributed
to parallel function of SERCA2 and NaCaX working at rates given by
pseudo-rate constants (
SR and
NCX where =ln 2/t1/2),
then during a twitch,
twitch=SR+NCX
and during a CafC,
CafC=NCX. Applying
this simple scheme to control contractions,
NCX is 1.41±0.49 s-1
and twitch is 4.77±0.18
s-1, giving SR=3.36
s-1. This would suggest 29% of
Ca2+ removal during a twitch in control rabbit
myocytes is by NaCaX (in close agreement with more detailed
quantitative analysis23 ). In HF cells,
NCX is increased to 2.34±0.26
s-1 and twitch is
comparable at 4.9±0.3 s-1, giving a reduced
SR of 2.54 s-1. This
change in SR (from 3.36 to 2.54) would imply a
24% reduction in SERCA2 function. Furthermore, the balance between the
SERCA2 and the NaCaX is changed in HF (so
NCX~SR) such that
they contribute about equally to twitch relaxation (ie, NaCaX component
increases from control of 29% to 48% in HF). Analysis of the
Ca2+ transient data yields a similar conclusion
(17% reduction in SERCA2 function). Thus we cannot rule out a small
reduction in SERCA2 function in the HF versus control rabbits.
Twitch Amplitude and SR Ca2+ Content
Twitches from HF myocytes were 26% smaller in amplitude compared
with control (12.9±1.2% versus 17.4±1.3% of resting cell length,
P<0.02; Table 2). The amplitude of CafC provides an
index of the SR Ca2+ content, and the mean value
was only 8% smaller in HF (24.6% versus 26.5% of resting cell
length, P=not significant). This raises the
possibility that there is a reduction in fractional SR
Ca2+ release in HF. However, using the ratio of
twitch:CafC amplitude as a crude index of fractional SR
Ca2+ release, we found no significant difference
between HF and control.
There was no difference in resting
[Ca2+]I between the
groups. The amplitude of twitch Ca2+ transients
was 30% smaller in HF versus control cells (Table 2). This is
comparable with the depression of twitch contractions and LV fractional
shortening but was not significant (possibly due to greater variance in
[Ca2+]i measurements).
The 11% decrease in CafC
[Ca2+]i was not
significantly different (but again comparable with contraction
results). The twitch:CafC ratio for
[Ca2+]i was not
significantly different between control and HF. Because the results for
contraction and Ca2+ transients are relatively
similar, we have no evidence of altered myofilament
Ca2+ sensitivity in HF (although not measured
directly). These results suggest that the reduction of twitch amplitude
in HF is likely to be due to decreased Ca2+
transients. Reduced Ca2+ transients could, in
principle, be due to reduced ICa trigger,
lower SR Ca2+ load (possible based on the CafC
data), or a depression of the E-C coupling process.
Measurement of ICa and NaCaX Current in
Isolated Myocytes
Voltage clamp experiments were carried out to evaluate
ICa (with respect to the issue of E-C
coupling above) and also to measure INa/Ca
under well controlled experimental conditions (to further verify the
expression and functional results above). Figure 8A shows the central protocol used, where
[Ca2+]i was buffered to
100 nmol/L to minimize alterations in
[Ca2+]i during protocols.
The conditions were also selected so that Ca, Na, and NaCaX currents
should be the only ones available. From an initial holding potential of
-90 mV, the cell was depolarized to -45 mV to activate and
inactivate Na current. Then a step from -45 to 0 mV was
used to activate and inactivate
ICa. Finally, the voltage was stepped to 80
mV and ramped down to -140 mV to assess
INa/Ca. The protocol was repeated in the
presence of 5 mmol/L Ni (Figure 8A) to obtain Ni-sensitive
ICa and INa/Ca
(Figure 8B).
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Figures 8C and 8D show that both inward and outward
INa/Ca are increased by 2.2-fold in HF. The
apparent reversal potential is unchanged and close to the predicted
value based on the pipette and extracellular solutions. This is
consistent with the above data based on mRNA, protein,
[Ca2+]i decline, and
relaxation of CafC (see Figure 9).
The amplitude of ICa was unchanged during
the pulses to 0 mV (Figure 8E). Some additional cells were also
studied with standard ICa protocols to
determine the voltage dependence of ICa
(Figure 8F). There was no difference in either
ICa amplitude or voltage dependence. The
ICa results suggest that depressed
Ca2+ transients and contractions in HF were not
attributable to altered ICa. Moreover,
ICa density stayed remarkably constant
despite the cellular hypertrophy in the HF cells.
Figures 9 and 10 summarize
results from the different approaches used here to assess NaCaX and
SERCA2 expression and function in control and HF. All of the data are
consistent with an approximate doubling of NaCaX expression and
function. In contrast, the results do not indicate any significant
change in SERCA2 expression, although there might be a small decrease
in function.
Correlation of NaCaX Functional Expression and SR
Ca2+ Content
An increase in NaCaX expression (with all other things remaining
the same) might be expected to reduce the steady-state SR
Ca2+ content (because NaCaX would compete better
with the SERCA2 during
[Ca2+]i decline and
diastole). Although hearts used for cell isolation were not
used for Western blotting, we can use the t1/2 of
relaxation of CafC as a functional index of NaCaX level in a given
cell. Figure 11 shows that the greater
the functional expression of NaCaX (smaller t1/2 CafC
values), the lower the SR Ca2+ content. Despite
substantial cellular heterogeneity, the correlation was
significant (P=0.015). Thus increased NaCaX expression may
contribute to unloading the SR of Ca2+ in the
steady state. There was no comparable correlation between twitch
amplitude and functional expression of NaCaX.
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Based on the results above, the depression of twitch amplitude in HF myocytes does not seem to be due to alteration of ICa. There does seem to be a tendency toward lower SR Ca2+ content in HF. This by itself might explain the reduced twitch amplitude. However, altered E-C coupling cannot be completely ruled out because an altered SR Ca2+ load makes it more difficult to assess E-C coupling directly (see Discussion).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of the present study demonstrate that this arrhythmogenic rabbit model of nonischemic cardiomyopathy is associated with an upregulation of NaCaX both on an mRNA and a protein level. The results in this model are in agreement with findings of NaCaX upregulation in myocardium from patients with end-stage HF.10 11 This concurrent upregulation of NaCaX on both an mRNA and a protein level and the strong association between mRNA and protein levels all suggest that this upregulation likely occurs at a pretranslational level. This NaCaX upregulation is carried forward in isolated myocytes as faster [Ca2+]i decline during CafC and greater INa/Ca. This enhanced NaCaX function may be involved in both the mechanical dysfunction and arrhythmogenic characteristics in this model of HF.
Functional Increase in NaCaX Activity in Failing Myocytes
In normal rabbit ventricular myocytes, relaxation and
[Ca2+]i decline are
attributable to the following 4 competing Ca2+
removal systems: 1) SERCA2, 2) NaCaX, 3) sarcolemmal
Ca2+-ATPase, and 4) mitochondria
Ca2+ uniporter.22 23 Bassani et
al23 analyzed the relative contributions
quantitatively, concluding that the SERCA2 removed 70%, NaCaX 28%,
and the others totaled only ~2%. The data from control hearts in the
present study (29% NaCaX) agree well with those conclusions.
However, the functional upregulation of NaCaX in HF shown here shifts
this balance such that Ca2+ removal is closer to
50% SERCA2 and 50% NaCaX during twitch relaxation. The increase in
NaCaX may well contribute to mechanical dysfunction and a larger inward
INa/Ca could also contribute directly to
arrhythmogenesis (see below).
Altered NaCaX expression and activity has been noted in experimental models of HF and in the failing human heart. Dogs with pacing-induced HF exhibit an increase in NaCaX protein and function (during [Ca2+]i decline).25 Rabbits with pacing-induced HF had a 44% increase in NaCaX protein but normal INa/Ca.26 In contrast, Yao et al27 found decreased NaCaX mRNA and ICa in a similar model.27 Increased INa/Ca has been demonstrated in myocytes from cardiomyopathic Syrian hamsters28 and infarcted rabbits.29 Several studies have shown an increase in both NaCaX mRNA and protein in myocardium from patients with end-stage HF obtained at the time of cardiac transplantation.10 11 Although little human functional data are available, Pieske et al30 recently showed a similar shift in NaCaX:SERCA2 function in human HF (from 25%:75% to ~50%:50%).
Hasenfuss et al31 recently showed that in human HF, upregulation of NaCaX protein correlated with a relative lack of LV diastolic dysfunction. This is consistent with our results in which twitch relaxation and [Ca2+]i decline were maintained and NaCaX was functionally increased in HF rabbits, but we did not directly evaluate diastolic function in vivo.
High Molecular Weight Transcript of NaCaX mRNA
In the present study, 4 of the 8 HF rabbits demonstrated a
high molecular weight (
14 kb) transcript of the NaCaX mRNA using a
cDNA probe that recognizes cardiac NaCaX mRNA. We found this transcript
at very low levels in only one of the controls, and in rabbit brain and
kidney, but not in skeletal muscle (data not shown). A similar 14-kb
transcript was detected in mouse heart and kidney32 ;
rabbit heart, kidney, and brain33 ; and human
brain34 but not in myocardium from patients
with end-stage HF.10 11 It remains to be determined as to
whether this 14-kb transcript is due to alternative splicing of NCX1
(the gene for NaCaX) or a long poly-A tail on some NaCaX mRNA and as to
what its role is. However, the 2-fold increase in the 7-kb NaCaX
transcript in the HF rabbits provides evidence that enhanced functional
NaCaX activity is due to a generalized increase in NaCaX expression and
not solely to increased expression of the high molecular weight
transcript.
SERCA2 Expression
In this rabbit model of nonischemic HF, we found no change
in SERCA2 mRNA or protein expression. Function of the SERCA2 based
directly on the rate of twitch relaxation and
[Ca2+]i decline was
apparently unaltered in HF versus control myocytes. However, more
detailed analysis (see Results) indicated that there might be a
modest functional depression of SERCA2 in the HF myocytes (but smaller
than the change in NaCaX). Although downregulation of SERCA2 had been
reported in several experimental models of HF35 36 and in
myocardium from patients with HF,14 15 other
studies have failed to demonstrate this effect.37 38 39
Of course reduced SERCA2 function alone would tend to reduce SR Ca2+ content, lower SR Ca2+ release, and slow relaxation of twitches. However, the dynamic interplay between the SERCA2 and NaCaX compels one to consider Ca2+ balance in a more integrated context.
Mechanical Dysfunction
Diastolic dysfunction usually refers to either a
slowing of relaxation or elevation of diastolic pressure.
In isolated ventricular myocytes, there was no change in
diastolic
[Ca2+]i. Neither twitch
relaxation nor [Ca2+]i
decline were slowed in this model of HF. On one hand, this unaltered
relaxation could be simply ascribed to an unaltered expression level of
SERCA2. On the other hand, the large and compelling increase in NaCaX
function would have been expected to accelerate
[Ca2+]i decline if SERCA2
did not change. Thus it is possible that the large increase in NaCaX
expression compensates for a small depression of SR
Ca2+ transport function (which could be hard to
detect and could also be due to factors other than protein levels, such
as phosphorylation state).
Systolic dysfunction can also result from alterations in
Ca2+ transport mechanisms. In the HF cells, there
was no change in ICa, which is expected to
be the central trigger for SR Ca2+ release.
However, there have been reports of depressed response of SR
Ca2+ release to a given
ICa trigger in certain models of
hypertrophy and HF.40 41 The shift in
balance between NaCaX and SERCA2 function would also mean that for a
given Ca2+ transient, there would be greater
extrusion from the cell and less refilling of the SR. This would be
expected to result in a lower steady state level of SR
Ca2+ loading, consistent with our results
from CafC amplitudes. Although the decreases in CafC and
[Ca2+]i in Table 2 were not significant, there was a significant inverse
correlation between NaCaX function and CafC amplitude (Figure 11). A lower SR Ca2+ load would decrease
SR Ca2+ release, and this could contribute to the
lower twitch contractions and Ca2+ transients
observed. Indeed, because fractional SR Ca2+
release depends steeply on SR Ca2+ content, a
modest depression of SR Ca2+ content could
decrease fractional release during E-C coupling to a greater
extent.42 Although the twitch/CafC ratios did not uncover
a significant E-C coupling defect, this issue should be more directly
addressed in controlled voltage clamp experiments.40 41
Greater extrusion of Ca2+ via NaCaX during the
twitch could also directly lower the twitch Ca2+
transient amplitude.23
Thus, although numerous possibilities cannot be explicitly ruled out,
our preferred working hypothesis is the following: systolic
function may be depressed simply because of reduced
Ca2+ transients that result from reduced SR
Ca2+ load, which is due to shifts in the balance
between NaCaX and SERCA2 (with unaltered
ICa, intrinsic E-C coupling gain, or
myofilament Ca2+ sensitivity). Causality is
difficult to prove, and it may be that increased NaCaX expression is
secondary to other factors in the failing heart, accounting for
heterogeneity in NaCaX expression (Figure 5 and
Reference 3131 ). Thus further tests of this hypothesis will be
required.
Spontaneous SR Ca2+ Release and
Arrhythmogenesis
In the intact animal, the lowered Ca2+
transients (and SR Ca2+ load) could be partially
offset by ß-adrenergic activation of the SERCA2. This may be
sufficient for the SR to reach an adequate Ca2+
load to produce relatively frequent spontaneous SR
Ca2+ release events (Ca2+
sparks or waves).43 44 Indeed, we found in HF myocytes
that treatment with isoproterenol increased the propensity for
spontaneous aftercontractions (Figure 2). Thus ß-adrenergic
agonists may offset a modest reduction in SR Ca2+
load in the myocytes and aftercontractions may be the cellular
manifestation of the enhanced arrhythmias in the intact HF
animals (Figure 1).5
Increased NaCaX in HF could also allow more Ca2+ influx, as an outward current early in the action potential, which could even contribute to triggering of SR Ca2+ release.29 45 46 More importantly, for a given SR Ca2+ release during an aftercontraction, the elevated NaCaX activity in HF myocytes would result in greater inward INa/Ca, contributing to Iti, DADs, and ultimately, nonreentrant VT as we see in the whole heart setting using 3D mapping.5 The specific role of upregulated NaCaX in the development of Iti remains to be determined, but our present findings support the hypothesis that an upregulated NaCaX may itself mediate enhanced Iti and the nonreentrant mechanism in this HF model.
Figure 12 illustrates our working
hypothesis based on increased arrhythmias and NaCaX in HF.
Local SR Ca2+ release elevates local
[Ca2+]I, which stimulates
Ca2+ extrusion via
INa/Ca. This Ca2+
extrusion produces an inward, depolarizing current
(Iti) that can produce a DAD, bringing the
diastolic membrane potential closer to threshold to trigger
an inappropriately timed action potential. With higher NaCaX activity
(as shown in the present study), any given amount of SR
Ca2+ release will result in greater inward
Iti and increased probability that a
triggered arrhythmia will result. It would be of interest to
explore whether arrhythmias are more prevalent in the
transgenic mouse that overexpresses NaCaX.45 47
|
Relevance of the Model of Nonischemic HF
In the present study, all of the HF rabbits had severe
depression of LV function, and 9 of 10 rabbits with serial Holter
monitoring demonstrated nonsustained VT. Additionally, we have found
that overall, ~10% of these HF rabbits have sudden death. These
findings reflect what is observed in patients with end-stage
nonischemic cardiomyopathy where 60% to
80% of patients exhibit nonsustained VT, and up to 40% to 45% will
die suddenly.1 This validates the use of this model to
study the cellular and molecular mechanisms underlying arrhythmogenesis
in the failing human heart. Indeed, this rabbit HF model seems to
combine aspects of both mechanical dysfunction and arrhythmogenic
potential that may be especially relevant to the failing human
heart.
Implications
The results of the present study suggest that an upregulation
of NaCaX expression and functional activity could contribute to both
mechanical dysfunction and arrhythmogenesis in the failing heart.
Upregulation of NaCaX could have an adaptive role in enhancing
Ca2+ efflux from myocytes (or possibly increasing
Ca2+ entry early in the development of HF).
However, with the progression of HF, this enhanced NaCaX activity may
limit SR Ca2+ loading and cellular
Ca2+ transients and also play a direct role in
the nonreentrant mechanisms underlying VT, which have been demonstrated
by 3D cardiac mapping. In the setting of enhanced NaCaX activity,
approaches to the treatment of HF in patients with drugs that either
increase intracellular [Na] (such as digitalis glycosides) or agents
that directly enhance NaCaX activity could have proarrhythmic effects
in the failing heart that would greatly limit their efficacy.
|
Acknowledgments |
|---|
This work was supported by NIH grants HL-46929 (S.M.P.) and HL-30077 and HL-52478 (D.M.B.). S.M.P. is an Established Investigator of the American Heart Association. The authors would like to thank Steven Scaglione for technical assistance and Barbara Donnelly for secretarial assistance.
Received August 5, 1999; accepted September 21, 1999.
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References |
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G. Munch, K. Rosport, C. Baumgartner, Z. Li, S. Wagner, A. Bultmann, and M. Ungerer Functional alterations after cardiac sodium-calcium exchanger overexpression in heart failure Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H488 - H495. [Abstract] [Full Text] [PDF]
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L.-S. Song, E. A. Sobie, S. McCulle, W. J. Lederer, C. W. Balke, and H. Cheng Orphaned ryanodine receptors in the failing heart. PNAS, March 14, 2006; 103(11): 4305 - 4310. [Abstract] [Full Text] [PDF]
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X. Ai, J. W. Curran, T. R. Shannon, D. M. Bers, and S. M. Pogwizd Ca2+/Calmodulin-Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphorylation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure Circ. Res., December 9, 2005; 97(12): 1314 - 1322. [Abstract] [Full Text] [PDF]
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A. D. Langenbacher, Y. Dong, X. Shu, J. Choi, D. A. Nicoll, J. I. Goldhaber, K. D. Philipson, and J.-N. Chen Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish PNAS, December 6, 2005; 102(49): 17699 - 17704. [Abstract] [Full Text] [PDF]
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S. Miyamoto, A. L. Howes, J. W. Adams, G. W. Dorn II, and J. H. Brown Ca2+ Dysregulation Induces Mitochondrial Depolarization and Apoptosis: ROLE OF Na+/Ca2+ EXCHANGER AND AKT J. Biol. Chem., November 18, 2005; 280(46): 38505 - 38512. [Abstract] [Full Text] [PDF]
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K. R. Sipido and D. Eisner Something old, something new: Changing views on the cellular mechanisms of heart failure Cardiovasc Res, November 1, 2005; 68(2): 167 - 174. [Full Text] [PDF]
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J. Bossuyt, X. Ai, J. R. Moorman, S. M. Pogwizd, and D. M. Bers Expression and Phosphorylation of the Na-Pump Regulatory Subunit Phospholemman in Heart Failure Circ. Res., September 16, 2005; 97(6): 558 - 565. [Abstract] [Full Text] [PDF]
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 S. Maeda, I. Matsuoka, T. Iwamoto, H. Kurose, and J. Kimura Down-Regulation of Na+/Ca2+ Exchanger by Fluvastatin in Rat Cardiomyoblast H9c2 Cells: Involvement of RhoB in Na+/Ca2+ Exchanger mRNA Stability Mol. Pharmacol., August 1, 2005; 68(2): 414 - 420. [Abstract] [Full Text] [PDF]
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H. Reuter, C. Pott, J. I. Goldhaber, S. A. Henderson, K. D. Philipson, and R. H.G. Schwinger Na+-Ca2+exchange in the regulation of cardiac excitation-contraction coupling Cardiovasc Res, August 1, 2005; 67(2): 198 - 207. [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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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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B. Bolck, G. Munch, P. Mackenstein, M. Hellmich, I. Hirsch, H. Reuter, N. Hattebuhr, H.-J. Weig, M. Ungerer, K. Brixius, et al. Na+/Ca2+ exchanger overexpression impairs frequency- and ouabain-dependent cell shortening in adult rat cardiomyocytes Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1435 - H1445. [Abstract] [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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L. Hove-Madsen, A. Llach, A. Bayes-Genis, S. Roura, E. R. Font, A. Aris, and J. Cinca Atrial Fibrillation Is Associated With Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes Circulation, September 14, 2004; 110(11): 1358 - 1363. [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.E Diaz, H.K Graham, and A.W Trafford Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy Cardiovasc Res, June 1, 2004; 62(3): 538 - 547. [Abstract] [Full Text] [PDF]
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Y. Wang and J. I. Goldhaber Return of calcium: Manipulating intracellular calcium to prevent cardiac pathologies PNAS, April 20, 2004; 101(16): 5697 - 5698. [Full Text] [PDF]
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S. Lafitte, S. Garrigue, J.-M. Perron, P. Bordachar, S. Reuter, P. Jais, M. Haissaguerre, J. Clementy, and R. Roudaut Improvement of left ventricular wall synchronization with multisite ventricular pacing in heart failure: a prospective study using Doppler tissue imaging Eur J Heart Fail, March 1, 2004; 6(2): 203 - 212. [Abstract] [Full Text] [PDF]
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H. Reuter, T. Han, C. Motter, K. D. Philipson, and J. I. Goldhaber Mice overexpressing the cardiac sodium-calcium exchanger: defects in excitation-contraction coupling J. Physiol., February 1, 2004; 554(3): 779 - 789. [Abstract] [Full Text] [PDF]
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A. Chorvatova, G. Hart, and M. Hussain Na+/Ca2+ exchange current (INa/Ca) and sarcoplasmic reticulum Ca2+ release in catecholamine-induced cardiac hypertrophy Cardiovasc Res, February 1, 2004; 61(2): 278 - 287. [Abstract] [Full Text] [PDF]
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H. Bader, S. Garrigue, S. Lafitte, S. Reuter, P. Jais, M. Haissaguerre, J. Bonnet, J. Clementy, and R. Roudaut Intra-left ventricular electromechanical asynchrony: A new independent predictor of severe cardiac events in heart failure patients J. Am. Coll. Cardiol., January 21, 2004; 43(2): 248 - 256. [Abstract] [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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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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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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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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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. Baartscheer, C. A. Schumacher, C. N.W. Belterman, R. Coronel, and J. W.T. Fiolet SR calcium handling and calcium after-transients in a rabbit model of heart failure Cardiovasc Res, April 1, 2003; 58(1): 99 - 108. [Abstract] [Full Text] [PDF]
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S. M Pogwizd, K. R Sipido, F. Verdonck, and D. M Bers Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis Cardiovasc Res, March 15, 2003; 57(4): 887 - 896. [Full Text] [PDF]
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W. Schillinger, J. W Fiolet, K. Schlotthauer, and G. Hasenfuss Relevance of Na+-Ca2+ exchange in heart failure Cardiovasc Res, March 15, 2003; 57(4): 921 - 933. [Full Text] [PDF]
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A Baartscheer, C.A Schumacher, C.N.W Belterman, R Coronel, and J.W.T Fiolet [Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure Cardiovasc Res, March 15, 2003; 57(4): 986 - 995. [Abstract] [Full Text] [PDF]
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W Schillinger, A Ohler, S Emami, F Muller, C Christians, P.M.L Janssen, H Kogler, N Teucher, B Pieske, T Seidler, et al. The functional effect of adenoviral Na+/Ca2+ exchanger overexpression in rabbit myocytes depends on the activity of the Na+/K+-ATPase Cardiovasc Res, March 15, 2003; 57(4): 996 - 1003. [Abstract] [Full Text] [PDF]
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R. Sah, R. J Ramirez, G. Y Oudit, D. Gidrewicz, M. G Trivieri, C. Zobel, and P. H Backx Regulation of cardiac excitation-contraction coupling by action potential repolarization: role of the transient outward potassium current (Ito) J. Physiol., January 1, 2003; 546(1): 5 - 18. [Abstract] [Full Text] [PDF]
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I. Sjaastad, J A. Wasserstrom, and O. M Sejersted Heart failure - a challenge to our current concepts of excitation-contraction coupling J. Physiol., January 1, 2003; 546(1): 33 - 47. [Abstract] [Full Text] [PDF]
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F. del Monte and R. J Hajjar Targeting calcium cycling proteins in heart failure through gene transfer J. Physiol., January 1, 2003; 546(1): 49 - 61. [Abstract] [Full Text] [PDF]
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T. R. Shannon, K. S. Ginsburg, and D. M. Bers Quantitative Assessment of the SR Ca2+ Leak-Load Relationship Circ. Res., October 4, 2002; 91(7): 594 - 600. [Abstract] [Full Text] [PDF]
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A. M. Gomez, B. Schwaller, H. Porzig, G. Vassort, E. Niggli, and M. Egger Increased Exchange Current but Normal Ca2+ Transport via Na+-Ca2+ Exchange During Cardiac Hypertrophy After Myocardial Infarction Circ. Res., August 23, 2002; 91(4): 323 - 330. [Abstract] [Full Text] [PDF]
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 W. Schillinger, H. Schneider, K. Minami, R. Ferrari, and G. Hasenfuss Importance of sympathetic activation for the expression of Na+-Ca2+ exchanger in end-stage failing human myocardium Eur. Heart J., July 2, 2002; 23(14): 1118 - 1124. [Abstract] [Full Text] [PDF]
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S. Despa, M. A. Islam, C. R. Weber, S. M. Pogwizd, and D. M. Bers Intracellular Na+ Concentration Is Elevated in Heart Failure But Na/K Pump Function Is Unchanged Circulation, May 28, 2002; 105(21): 2543 - 2548. [Abstract] [Full Text] [PDF]
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U. Wisloff, J. P. Loennechen, S. Currie, G. L. Smith, and O. Ellingsen Aerobic exercise reduces cardiomyocyte hypertrophy and increases contractility, Ca2+ sensitivity and SERCA-2 in rat after myocardial infarction Cardiovasc Res, April 1, 2002; 54(1): 162 - 174. [Abstract] [Full Text] [PDF]
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E. TAKIMOTO, A. YAO, H. TOKO, H. TAKANO, M. SHIMOYAMA, M. SONODA, K. WAKIMOTO, T. TAKAHASHI, H. AKAZAWA, M. MIZUKAMI, et al. Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload FASEB J, March 1, 2002; 16(3): 373 - 378. [Abstract] [Full Text] [PDF]
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K. R Sipido, P. G.A Volders, M. A Vos, and F. Verdonck Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res, March 1, 2002; 53(4): 782 - 805. [Abstract] [Full Text] [PDF]
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J. G. Muller, Y. Isomatsu, S. V. Koushik, M. O'Quinn, L. Xu, C. S. Kappler, E. Hapke, M. R. Zile, S. J. Conway, and D. R. Menick Cardiac-Specific Expression and Hypertrophic Upregulation of the Feline Na+-Ca2+ Exchanger Gene H1-Promoter in a Transgenic Mouse Model Circ. Res., February 8, 2002; 90(2): 158 - 164. [Abstract] [Full Text] [PDF]
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C. R. Weber, V. Piacentino III, K. S. Ginsburg, S. R. Houser, and D. M. Bers Na+-Ca2+ Exchange Current and Submembrane [Ca2+] During the Cardiac Action Potential Circ. Res., February 8, 2002; 90(2): 182 - 189. [Abstract] [Full Text] [PDF]
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S.-k. Wei, J. F Quigley, S. U Hanlon, B. O'Rourke, and M. C.P Haigney Cytosolic free magnesium modulates Na/Ca exchange currents in pig myocytes Cardiovasc Res, February 1, 2002; 53(2): 334 - 340. [Abstract] [Full Text] [PDF]
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J. L. Puglisi and D. M. Bers LabHEART: an interactive computer model of rabbit ventricular myocyte ion channels and Ca transport Am J Physiol Cell Physiol, December 1, 2001; 281(6): C2049 - C2060. [Abstract] [Full Text] [PDF]
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R. Shenoy, I. Klein, and K. Ojamaa Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1690 - H1696. [Abstract] [Full Text] [PDF]
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C. L. Elias, A. Lukas, S. Shurraw, J. Scott, A. Omelchenko, G. J. Gross, M. Hnatowich, and L. V. Hryshko Inhibition of Na+/Ca2+ exchange by KB-R7943: transport mode selectivity and antiarrhythmic consequences Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1334 - H1345. [Abstract] [Full Text] [PDF]
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J. Meszaros, D. Khananshvili, and G. Hart Mechanisms underlying delayed afterdepolarizations in hypertrophied left ventricular myocytes of rats Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H903 - H914. [Abstract] [Full Text] [PDF]
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S. Adachi-Akahane and Y. Kurachi New Era for Translational Research in Cardiac Arrhythmias Circ. Res., June 8, 2001; 88(11): 1095 - 1096. [Full Text] [PDF]
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M. Shigekawa and T. Iwamoto Cardiac Na+-Ca2+ Exchange : Molecular and Pharmacological Aspects Circ. Res., May 11, 2001; 88(9): 864 - 876. [Abstract] [Full Text] [PDF]
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 J. Yamashita, M. Itoh, T. Kuro, Y. Kobayashi, M. Ogata, M. Takaoka, and Y. Matsumura Pre- or Post-Ischemic Treatment with a Novel Na+/Ca2+ Exchange Inhibitor, KB-R7943, Shows Renal Protective Effects in Rats with Ischemic Acute Renal Failure J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 412 - 419. [Abstract] [Full Text]
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I. A. Hobai and B. O'Rourke Decreased Sarcoplasmic Reticulum Calcium Content Is Responsible for Defective Excitation-Contraction Coupling in Canine Heart Failure Circulation, March 20, 2001; 103(11): 1577 - 1584. [Abstract] [Full Text] [PDF]
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K. L. Golden, J. Ren, J. O'Connor, A. Dean, S. E. DiCarlo, and J. D. Marsh In vivo regulation of Na/Ca exchanger expression by adrenergic effectors Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1376 - H1382. [Abstract] [Full Text] [PDF]
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 C. R. Weber, K. S. Ginsburg, K. D. Philipson, T. R. Shannon, and D. M. Bers Allosteric Regulation of Na/Ca Exchange Current by Cytosolic Ca in Intact Cardiac Myocytes J. Gen. Physiol., February 1, 2001; 117(2): 119 - 132. [Abstract] [Full Text] [PDF]
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S. R Houser Reduced abundance of transverse tubules and L-type calcium channels: another cause of defective contractility in failing ventricular myocytes Cardiovasc Res, February 1, 2001; 49(2): 253 - 256. [Full Text] [PDF]
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K. R. Sipido Local Ca2+ Release in Heart Failure : Timing Is Important Circ. Res., November 24, 2000; 87(11): 966 - 968. [Full Text] [PDF]
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S. Nattel Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders Cardiovasc Res, November 1, 2000; 48(2): 188 - 190. [Full Text] [PDF]
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C. M.N Terracciano Sarcoplasmic reticulum calcium release function and FK binding proteins in heart failure: another piece of a complex jigsaw Cardiovasc Res, November 1, 2000; 48(2): 191 - 193. [Full Text] [PDF]
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S. R. Houser When Does Spontaneous Sarcoplasmic Reticulum CA2+ Release Cause a Triggered Arrythmia? Cellular Versus Tissue Requirements Circ. Res., October 27, 2000; 87(9): 725 - 727. [Full Text] [PDF]
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K. Schlotthauer and D. M. Bers Sarcoplasmic Reticulum Ca2+ Release Causes Myocyte Depolarization : Underlying Mechanism and Threshold for Triggered Action Potentials Circ. Res., October 27, 2000; 87(9): 774 - 780. [Abstract] [Full Text] [PDF]
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K. R. Sipido, P. G. A. Volders, S. H. M. de Groot, F. Verdonck, F. Van de Werf, H. J. J. Wellens, and M. A. Vos Enhanced Ca2+ Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular Myocytes : Potential Link Between Contractile Adaptation and Arrhythmogenesis Circulation, October 24, 2000; 102(17): 2137 - 2144. [Abstract] [Full Text] [PDF]
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S. M. Pogwizd Increased Na+-Ca2+ Exchanger in the Failing Heart Circ. Res., October 13, 2000; 87(8): 641 - 643. [Full Text] [PDF]
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I. A. Hobai and B. O'Rourke Enhanced Ca2+-Activated Na+-Ca2+ Exchange Activity in Canine Pacing-Induced Heart Failure Circ. Res., October 13, 2000; 87(8): 690 - 698. [Abstract] [Full Text] [PDF]
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P. Trouve, F. Carre, I. Belikova, C. Leclercq, T. Dakhli, L. Soufir, I. Coquard, J. Ramirez-Gil, and D. Charlemagne Na+-K+-ATPase alpha 2-isoform expression in guinea pig hearts during transition from compensation to decompensation Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1972 - H1981. [Abstract] [Full Text] [PDF]
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W. H. Barry Na+-Ca2+ Exchange in Failing Myocardium : Friend or Foe? Circ. Res., September 29, 2000; 87(7): 529 - 531. [Full Text] [PDF]
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S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]
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D. M. Bers Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction Circ. Res., August 18, 2000; 87(4): 275 - 281. [Full Text] [PDF]
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