Effects of inhibiting Na / H -exchange or angiotensin converting

Cardiovascular Research 54 (2002) 438–446
www.elsevier.com / locate / cardiores
Effects of inhibiting Na 1 / H 1 -exchange or angiotensin converting
enzyme on atrial tachycardia-induced remodeling
Kaori Shinagawa a , Hideo Mitamura b , Satoshi Ogawa b , Stanley Nattel a,c , *
a
Department of Medicine, University of Montreal, and Montreal Heart Institute Research Center, 5000 Belanger Street East, Montreal, Quebec,
Canada H1 T 1 C8
b
Cardiopulmonary Division, Keio University School of Medicine, Tokyo, Japan
c
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Received 23 August 2001; accepted 18 October 2001
Abstract
Keywords: Antiarrhythmic agents; Arrhythmia (mechanisms); ECG; Ion exchangers; Renin–angiotensin system
1. Introduction
Atrial fibrillation (AF) is currently the most common
sustained arrhythmia in clinical practice. It has been shown
that AF alters atrial electrophysiology to promote its own
maintenance, a process often referred to as electrophysiological remodeling [1]. Sustained atrial tachycardia causes
*Corresponding author. Tel.: 11-514-376-3330; fax: 11-514-3761355.
E-mail address: [email protected] (S. Nattel).
a variety of electrophysiological alterations, including
atrial effective refractory period (ERP) abbreviation, that
promote AF inducibility and maintenance [1–5]. There is
evidence for Ca 21 overload as an initiating signal for
tachycardia-induced remodeling [6–9].
Because of the limitations of presently available therapy,
there has been an interest in developing novel approaches
to AF therapy. One potentially interesting possibility is the
use of drugs to prevent atrial electrical remodeling. The
T-type Ca 21 -channel blocker mibefradil strongly inhibits
Time for primary review 27 days.
0008-6363 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 01 )00515-6
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Background: Inhibitors of the Na 1 / H 1 -exchanger (NHE1) and of angiotensin-converting enzyme (ACE) have been shown to reduce
short-term (,6 h) tachycardia-induced atrial electrical remodeling. The role of NHE1 and ACE in longer-term electrical remodeling, as
might occur with persistent AF, has not been studied. Methods: Dogs were subjected to atrial-tachypacing (400 bpm) for 7 days during
treatment with 240 mg / day (standard clinical dose) of the NHE1 inhibitor cariporide (CariL, n56), 1000 mg / day cariporide (CariH,
n56), 2 mg / kg / day of the ACE inhibitor enalapril (E, n56), or no-drug controls (n57). To ensure steady state concentrations at the
onset of pacing, treatment began 3 days before the initiation of atrial tachypacing. Results were compared to those of unpaced dogs
(n59). Results: Atrial tachypacing reduced atrial effective refractory period (ERP), e.g. at a basic cycle length of 300 ms from 12664 ms
(unpaced, mean6S.E.) to 7968 ms (no-drug controls, P,0.001). ERP abbreviation was unchanged by CariL (8368 ms), CariH (8067
ms), or E (7665 ms). Atrial tachypacing increased mean duration of the longest AF episode in each dog (DAF) from 130680 s (unpaced)
similarly in all groups: 8646364 s, no-drug controls; 6096376 s, CariL; 7096353 s, CariH; 6456365 s, E (P5NS for differences among
groups). Sustained AF requiring cardioversion for termination was induced in 0% of unpaced dogs vs. 33% of CariL, 33% of CariH, 33%
of E, and 43% of control dogs. AF inducibility by single extrastimuli increased from 462% in unpaced dogs to 48613% (P,0.01) in
no-drug control dogs, an effect not changed by CariL (33614%), CariH (35617%) or E (48616%). Conclusions: In contrast to
short-term (several-hour) atrial tachycardia-induced remodeling, remodeling by 7-day tachycardia is not affected by NHE1 or ACE
inhibition. These results support the notion that short-term atrial tachycardia remodeling involves different mechanisms from longer-term
remodeling, and urges caution in extrapolating results from studies of short-term remodeling to effects in longer-term remodeling as often
occurs clinically.  2002 Elsevier Science B.V. All rights reserved.
K. Shinagawa et al. / Cardiovascular Research 54 (2002) 438 – 446
2. Methods
2.1. Animal preparation
All animal-handling procedures were approved by the
animal research ethics committee of the Montreal Heart
Institute and followed the guidelines of the Canadian
Council on Animal Care. Twenty-five mongrel dogs
(weight, 23–40 kg) were initially anesthetized with
ketamine (5.3 mg / kg, i.v.), diazepam (0.25 mg / kg, i.v.)
and halothane (1–2%). Unipolar pacing leads were inserted in the right ventricular (RV) apex and the right atrial
(RA) appendage under fluoroscopic guidance. The leads
were connected to a ventricular pacemaker (model 8084 or
8086, Medtronic) and a custom-modified atrial tachypacemaker implanted in a subcutaneous pocket in the
neck. AV block was created by radiofrequency catheter
ablation to avoid excessively rapid ventricular responses
during atrial tachypacing, and the RV pacemaker was
programmed to capture the ventricles at 80 bpm. The right
atrium was stimulated at 400 bpm for 1 week.
Rapidly-paced dogs were treated with 240 mg / day of
cariporide, an NHE1 inhibitor (CariL, n56), 1000 mg / day
cariporide (CariH, n56), 2 mg / kg / day enalapril, an ACE
inhibitor (E, n56), or no drug (ND, n57), beginning 3
days before atrial pacemaker activation and continuing
until the morning of the electrophysiological study. The
240 mg / day dose of cariporide was selected because it is
the highest dose in clinical use. When our initial data
suggested a lack of cariporide effect at this dose, we
decided to study an additional series of dogs (CariH)
exposed to higher doses. To ensure therapeutic concentrations in the high-dose cariporide group, blood samples
were obtained for subsequent measurement of plasma
cariporide concentration at 0, 30, 60 and 90 min after the
morning dose on the day before electrophysiological study,
prior to the second dose on that day, and at the time of the
electrophysiological study. Cariporide concentrations were
measured by Aventis Pharma, Frankfurt, Germany. The
enalapril dose was based on a previous study we conducted
in which 2 mg / kg of enalapril produced highly-significant
reductions in CHF-induced atrial remodeling [24]. Nine
dogs were used as an unpaced control group, three of
which were instrumented and monitored like atrial tachypacing dogs but without pacemaker activation. The
results in these sham dogs were the same as in six acute
control animals; therefore the results of all nine unpaced
control dogs were grouped together for analysis purposes.
On study days, dogs were anesthetized with morphine (2
mg / kg, s.c.) and a-chloralose (120 mg / kg, i.v., followed
by 29.25 mg / kg / h) and ventilated to maintain physiological arterial blood gases (pH 7.38–7.45, SaO 2 .95%). In
atrial tachypacing dogs, the surface ECG was recorded to
confirm maintained atrial and ventricular pacing and AV
block. The atrial pacemaker was then deactivated. Body
temperature was maintained at 378C, and the left femoral
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atrial tachycardia-induced remodeling [10,11], but has
been withdrawn from the market because of adverse drug
reactions. Although L-type Ca 21 -channel blockers reduce
short-term atrial tachycardia remodeling (,24 h), they are
ineffective for remodeling by longer-lasting atrial tachycardias [11,12].
Recent work has focused on the potential role of two
important systems, the Na 1 / H 1 exchanger (NHE1) [13]
and the renin–angiotensin system [14]. There are similarities between the histological appearance of tissue from
atria that have been kept in AF for prolonged periods and
chronically-ischemic ventricular myocardium [15]. In addition, preliminary data have been presented that point to
reduced atrial blood flow in chronic AF [16]. Strong
activation of NHE1 results from the intracellular acidosis
during acute ischemia [17], and NHE1 stimulation plays an
important role in arrhythmias associated with acute ischemia [18,19], possibly by promoting Ca 21 -loading
[20,21]. These observations led Jayachandran et al. [13] to
evaluate the ability of cariporide, an NHE1 inhibitor
previously known as HOE642, to prevent atrial tachycardia-induced remodeling. They found that cariporide
prevented effective refractory period (ERP) abbreviation
occurring within 30 min of atrial pacing at 600 bpm, and
concluded that NHE1 might be involved in short-term
tachycardia-induced remodeling.
Pedersen et al. [22] have shown that the angiotensinconverting enzyme (ACE) inhibitor trandolapril reduces
the prevalence of AF after acute myocardial infarction in
patients with left ventricular dysfunction. The mechanism
of this benefit is unknown. Based on their own unpublished observations that the non-ACE angiotensin-II forming enzyme chymase is more strongly expressed in the left
atrium than in other cardiac chambers, Nakashima et al.
[14] evaluated the effects on atrial tachycardia-remodeling
of blocking angiotensin-1 (AT 1 ) receptors and inhibiting
ACE. They found that atrial tachypacing at 800 bpm
decreased atrial ERP over 120 min, an effect that could be
mimicked by angiotensin-II infusion and could be blocked
by the AT 1 -receptor antagonist candesarten as well as the
ACE inhibitor capropril.
These observations suggest that either NHE1 or ACE
inhibition can prevent short-term (,2 h) tachycardia-induced atrial electrical remodeling. Since NHE1 and ACE
inhibitors are available for clinical development, they
could be used for AF therapy if they effectively prevented
remodeling; however, the efficacy of NHE1 and ACE
inhibitors in longer-term electrical remodeling, as might
occur with persistent AF, has not been studied. In order to
address this issue, we examined the effects of the NHE1
inhibitor cariporide and the ACE inhibitor enalapril on
atrial electrophysiological remodeling caused by 7 days of
rapid atrial pacing in the dog. A 7-day pacing period was
chosen because L-type Ca 21 current (ICaL ) downregulation
is quite significant after 7 days, with only small additional
decreases noted after 42 days of rapid pacing [23].
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K. Shinagawa et al. / Cardiovascular Research 54 (2002) 438 – 446
artery and both femoral veins were cannulated for pressure
monitoring and drug administration. A median sternotomy
was performed, and bipolar, Teflon-coated stainless steel
electrodes were inserted into the RA and left atrial (LA)
appendages for recording and stimulation. A programmable stimulator (Digital Cardiovascular Instruments) was
used to deliver 2-ms pulses at twice-threshold current. Five
thin silicon plaques containing 240 bipolar electrodes were
sewn into position to cover the atrial epicardial surface,
and stimulation and recording were performed as previously described [25].
wavelength was calculated as the product of local CV and
local ERP [26].
Statistical comparisons of multiple group means were
obtained by analysis of variance (ANOVA). A t-test with
Bonferroni correction was used to evaluate the significance
of differences between individual mean values. Average
results are given as the mean6S.E.M., and a two-tailed
P,0.05 was considered statistically significant.
3. Results
3.1. Changes in properties of AF
2.2. Electrophysiological study
Dogs subjected to 7 days of rapid atrial pacing without
drug therapy had significantly increased AF duration
(8646364 s, P,0.05) compared to unpaced dogs
(129680 s). AF duration of enalapril-treated dogs
(6456365 s), low-dose cariporide dogs (6096376 s) and
high-dose cariporide-treated dogs (7096352 s) were not
significantly different from no-drug atrial tachypacing
dogs. Persistent AF was noted in three of seven (43%)
no-drug dogs, two of six (33%) enalapril dogs, two of six
(33%) low-dose cariporide dogs and two of six (33%)
high-dose cariporide dogs vs. none (0%) of unpaced dogs.
Fig. 1 shows vulnerability to AF induction by single atrial
premature extrastimuli. A single premature extrastimulus
was able to induce AF at 47.9% of sites in no-drug
tachypaced dogs, 47.9% in enalapril dogs, 33.3% in lowdose and 35.4% in high-dose cariporide dogs, with each
2.3. Data analysis
Conduction velocity (CV) was determined by analyzing
activation at four electrode sites in the direction of rapid
propagation. Distance from the proximal site was plotted
against activation time, and CV was determined from the
slope of the best-fit regression line [4,24], with a clear
linear relation (r.0.99) required for analysis. The local
Fig. 1. Mean6S.E.M. percentage vulnerability to AF induction by single
atrial premature extrastimuli in various groups. Vulnerability in no-drug
tachypaced, enalapril (E), low (CariL) and high (CariH) dose cariporide
dogs was significantly greater than in control dogs.
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The ERP was measured at the LA and the RA appendages with 15 basic (S1) stimuli at basic cycle lengths
(BCLs) of 150, 200, 250, 300 and 360 ms, followed by a
premature (S2) stimulus, with the ERP defined as the
longest S1S2 interval failing to produce a response. The
mean of three ERP values at each BCL was used for data
analysis. In the case of a $10-ms difference between each
measurement, one or two additional ERP measurements
were obtained, and the mean of all determinations was
used. To evaluate regional ERP properties, ERPs were
measured at a BCL of 300 ms at seven sites: RA
appendage, RA posterior wall, RA inferior wall, LA
appendage, LA posterior wall, LA inferior wall, and
Bachmann’s bundle.
AF was induced by stimulating the atrium with up to
three consecutive extrastimuli at a BCL of 150 ms and
then atrial burst pacing (10 Hz, 2-ms stimuli at four times
threshold current for 1–10 s). To obtain an index of AF
duration, AF was induced ten times if AF duration was
#20 min and five times if AF lasted between 20 and 30
min. AF that lasted .30 min, which was considered
persistent, was terminated by DC electrical cardioversion,
and 30 min was allowed before the experiment was
continued. If persistent AF was induced on two occasions,
no further AF inductions were performed. We found that
the longest AF period in each dog was the most consistent
index of AF duration for each group. The mean duration of
longest AF episodes per dog was therefore used as the
index of AF duration to characterize each group. Atrial
vulnerability was defined as the percentage of sites in each
dog at which AF could be induced by single extrastimuli.
K. Shinagawa et al. / Cardiovascular Research 54 (2002) 438 – 446
value in atrial tachypaced dogs significantly greater than in
unpaced dogs (4.2%, P,0.01 for no-drug and enalapril
dogs, P,0.05 for each cariporide group; P5NS among all
tachypaced groups).
441
atrial tachycardia-induced remodeling were not due to
inadequate plasma concentrations.
4. Discussion
3.2. Changes in electrophysiological variables
3.3. Plasma cariporide concentrations
Mean plasma cariporide levels in high-dose cariporide
treated dogs averaged 1.660.3, 2.360.9, 4.661.4, and
5.961.6 mg / ml at 0, 30, 60 and 90 min after the morning
dose on the day before electrophysiological study, 4.860.7
mg / ml prior to the second dose on that day, and 1.560.4
mg / ml at the time of the electrophysiological study,
respectively. All of these concentrations were greater than
the concentration (0.55 mg / ml) required for complete
NHE1 blockade (Aventis Pharma, unpublished data).
Therefore, the lack of important effects of cariporide on
In the present study, we have evaluated the effects of
inhibiting NHE1 and ACE by oral therapy with enalapril
and cariporide on the atrial remodeling induced by 7 days
of atrial tachypacing. We found that, despite evidence for
benefit from these drugs against short-term remodeling,
they have no significant protective effects against the ERP
reduction, abolition of rate-adaptation, and increases in AF
duration and atrial vulnerability produced by a week of
atrial tachycardia.
4.1. Relationship to previous observations regarding
atrial tachycardia-induced remodeling
Recent studies in animal models and humans have
shown that atrial tachycardia (whether as a result of rapid
1:1 pacing or maintained AF) produces shortening of the
atrial ERP and loss of physiological ERP rate adaptation
[1–5,10,11]. Changes in CV with long-term (several-week)
atrial pacing have been variable, however, no studies have
shown that atrial tachycardia slows conduction in normal
hearts significantly over a 1-week period. In this study, we
found shortening of atrial ERP and loss of ERP rate
adaptation produced by rapid pacing that parallels previous
reports in animal models of AF as well as human experiments.
Although the mechanisms underlying atrial tachycardiainduced remodeling in normal hearts are incompletely
understood, decreases in ICaL density resulting from sustained rapid activation likely contribute importantly to
changes in atrial ERP and ERP rate-adaptation [23].
Intracellular Ca 21 overload is thought to contribute to this
phenomenon [6–8,19,27,28]. The ICaL blocker verapamil
prevents atrial ERP shortening and AF promotion caused
by short-term AF (5–15 min) in man [7,8]; however,
despite reducing ERP abbreviation caused by 24 h of atrial
tachypacing, verapamil does not substantially alter the
attendant increase in vulnerability to AF induction [28].
Verapamil has no effect on ERP or AF vulnerability
changes induced by 1 and 6 weeks of atrial tachycardia
[12]. Whereas the selective T-type Ca 21 channel blocker
mibefradil protects against atrial remodeling caused by
7-day atrial tachycardia, the L-type Ca 21 channel blocker
diltiazem is not effective [10,11]. These reports indicate
that the efficacy of an intervention for remodeling by
short-term atrial tachycardia (minutes or hours) does not
necessarily imply efficacy against remodeling induced by
longer durations (.24 h) of atrial tachyarrhythmia. This
observation is consistent with evidence that the mecha-
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Fig. 2A shows ERP values at various BCLs in the RA
appendage (left) and LA appendage (right) for all groups.
Atrial tachypaced no-drug dogs, enalapril-treated tachypaced dogs, and cariporide-treated tachypaced dogs had
significantly reduced ERP at all BCLs at either site
compared to unpaced dogs (P,0.01 for each). All groups
of tachypaced dogs had the ERP changes characteristic of
atrial tachycardia-induced remodeling in normal hearts as
described previously [1–5]: decreased ERP and loss of
ERP rate-adaptation. Fig. 2B shows mean CV values in RA
(left) and LA (right). These were unaltered in any atrial
tachypaced group and were consistent with the results of
previous studies in the 7-day atrial tachycardia remodeling
setting [4]. Wavelength changes in the RA (Fig. 2C, left)
and LA (Fig. 2C, right) largely reflected ERP alterations,
with wavelength significantly decreased in all tachypaced
groups and with no significant differences among groups
treated with different drugs.
Fig. 3A displays an analysis of atrial ERP values at a
single BCL (300 ms) in seven different atrial regions.
Although the degree of remodeling varied among regions,
atrial tachypacing significantly reduced atrial ERP compared to unpaced controls at all sites in each tachypaced
group. Results were not significant among tachypaced
groups. Fig. 3B displays the regional distribution of CV at
a BCL of 300 ms. There were small but inconsistent
differences among groups and CV was not affected overall.
Fig. 3C provides mean data for wavelength in the four
areas for which CV was obtained in each group. Wavelength significantly decreased in all zones in all tachypaced
dogs. The changes in Bachmann’s bundle were quantitatively smaller in low-dose cariporide treated dogs, but the
value at this site in this group remained statistically
significantly different compared to unpaced dogs.
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K. Shinagawa et al. / Cardiovascular Research 54 (2002) 438 – 446
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Fig. 2. Mean6S.E.M. electrophysiological data as a function of BCL in RA (left) and LA (right) appendages. Tachypaced dogs receiving no drug,
enalapril (E), low (Cari L) and high (CariH) dose cariporide had significantly reduced ERP (A) and ERP rate-adaptation at all BCLs at either site compared
to unpaced controls. CV values were not significantly different among groups (B). Like ERP, wavelength (C) was significantly decreased in no-drug,
enalapril, and cariporide dogs compared to unpaced controls.
K. Shinagawa et al. / Cardiovascular Research 54 (2002) 438 – 446
443
4.2. Effects of ACE and NHE1 inhibition on atrial
electrical remodeling and AF
nisms underlying long-term atrial tachycardia-induced
remodeling are different from those of short-term remodeling [29].
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Fig. 3. Regional distribution of ERP (A), CV (B) and wavelength (C) in
various groups. RAA, LAA5RA, LA appendage; RAPW, LAPW5RA,
LA posterior wall; RAIW, LAIW5RA, LA inferior wall; BB5
Bachmann’s bundle.
The ACE inhibitor trandolapril has been shown to
reduce the occurrence rate of AF in post-myocardial
infarction patients with left ventricular dysfunction [22].
The mechanism of AF prevention by this ACE inhibitor is
unknown; however, there is evidence for a role of the
renin–angiotensin system in clinical AF. Goette et al. [30]
have observed increased ACE expression and alterations in
angiotensin II receptor expression [31] in atrial tissues of
patients with AF. Recently, Nakashima et al. [14] reported
that intravenous administration of the ACE inhibitor
captopril or the angiotensin II type 1 receptor (AT1)
antagonist candesartan prevents the shortening of atrial
ERP and loss of ERP rate adaptation caused by 180 min of
atrial tachypacing. The results of Nakashima’s study
suggest that inhibition of atrial tachycardia-induced remodeling could have contributed to the clinical benefits
against AF observed with trandolapril. The results of the
present study argue that beneficial effects against tachycardia-remodeling are unlikely to be the principal mechanism of ACE inhibitor efficacy in AF. Li et al. [32] have
shown that oral enalapril reduces mitogen activated protein
kinase activation, atrial fibrosis and AF promotion in a dog
model of CHF. This observation provides an alternative
explanation for the therapeutic benefits of ACE inhibition
in AF: the prevention of atrial structural remodeling.
NHE1 plays a key role in a variety of cardiac injury
states, particularly those associated with myocardial ischemia and reperfusion [33]. NHE1 inhibition has been
shown to have beneficial effects on myocardial remodeling
and CHF after myocardial infarction [34] and to promote
conversion of VF in a rat model [35]. Jayachandran et al.
[13] showed that the atrial ERP abbreviation and loss of
ERP rate adaptation produced by atrial pacing at 600 bpm
for 5 h in dogs were prevented by the NHE1 inhibitor
HOE642 (cariporide). In addition, acute atrial ischemia
produced by right coronary artery occlusion produced
shortening of the right atrial ERP and loss of ERP rate
adaptation, which were also prevented by NHE1 blockade.
These findings were interpreted as pointing to a potential
role for NHE1 activation by ischemia in atrial electrical
remodeling caused by 5 h of atrial tachypacing. Similarly,
cariporide was found to attenuate atrial contractile
dysfunction caused by short-term atrial tachycardia [36].
Cariporide is well-tolerated in man and has been studied in
a large multicenter trial of patients with acute coronary
syndromes [37]. Therefore, if cariporide were beneficial in
preventing atrial tachycardia remodeling, it would be
potentially quite useful in AF. Unfortunately, the results of
the present study were disappointing in this regard — no
benefit against atrial remodeling was observed from
cariporide in dogs exposed to 7 days of atrial tachycardia,
even at a dose demonstrated by plasma concentration
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K. Shinagawa et al. / Cardiovascular Research 54 (2002) 438 – 446
measurements to maintain effective concentrations of the
drug at all times.
4.3. Novel findings and potential significance
4.4. Potential limitations
The present study evaluated electrical remodeling induced by 7 days of atrial tachycardia. This tachypacing
duration was selected because ionic remodeling is near
steady state after 7 days of tachycardia [23]. Although we
cannot exclude the possibility that results might have been
different for a different tachypacing duration, the absence
of any clear effect in the present study suggests that the
process of ionic remodeling underlying longer-term atrial
tachycardia remodeling was not significantly altered.
Acknowledgements
This work was supported by the Canadian Institutes of
Health Research (CIHR), the Mathematics of Information
Technology and Complex Systems (MITACS) Network of
Centers of Excellence and the Quebec Heart and Stroke
Foundation. Kaori Shinagawa is a CIHR fellow. The
authors thank Aventis Pharma, Frankfurt, for providing
cariporide and for performing the measurements of
cariporide plasma concentrations, Chantal Maltais and
Nathalie L’Heureux for technical assistance, and France
´
Theriault
for secretarial help with the manuscript. They
also thank Merck Laboratories for providing the enalapril
used in these studies.
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This is the first study of which we are aware to evaluate
the effects of inhibiting NHE1 and ACE on long-term
atrial tachycardia-induced remodeling. The results suggest
that neither NHE1 inhibition nor ACE inhibition alone is
sufficient to prevent remodeling caused by 7 days of atrial
tachycardia. Although this result is disappointing, the study
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Short-term studies of atrial tachycardia-remodeling are
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in patients with left ventricular dysfunction post-myocardial infarction. The studies of Li et al. [32] provide an
alternative explanation, the inhibition of structural remodeling. The basis for benefit in short-term atrial tachycardia remodeling seen by Nakashima et al. [14] is unclear
and merits further study.
K. Shinagawa et al. / Cardiovascular Research 54 (2002) 438 – 446
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