Vol. 277, Issue 4, H1429-H1434, October 1999
-Blockade improves adjacent regional sympathetic
innervation during postinfarction remodeling
Christopher M.
Kramer1,
Philip
D.
Nicol1,
Walter J.
Rogers1,
Philip S.
Seibel2,
Chong S.
Park2, and
Nathaniel
Reichek1
1 Division of Cardiology,
Department of Medicine, and
2 Division of Cardiothoracic
Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania 15212
 |
ABSTRACT |
The effect of
-blockade on left ventricular (LV) remodeling, when added to
angiotensin-converting enzyme inhibition (ACEI) after anterior
myocardial infarction (MI), is incompletely understood. On
day 2 after coronary ligation-induced
anteroapical infarction, 17 sheep were randomized to ramipril (ACEI,
n = 8) or ramipril and metoprolol
(ACEI-, n = 9). Magnetic resonance
imaging was performed before and 8 wk after MI to measure changes in LV
end-diastolic, end-systolic, and stroke volume indexes, LV mass index,
ejection fraction (EF), and regional percent intramyocardial
circumferential shortening.
123I-labeled
m-iodobenzylguanidine (MIBG) and
fluorescent microspheres before and after adenosine were infused before
death at 8 wk post-MI for quantitation of sympathetic innervation,
blood flow, and blood flow reserve in adjacent and remote noninfarcted
regions. Infarct size, regional blood flow, blood flow reserve, and the
increase in LV mass and LV end-diastolic and end-systolic volume
indexes were similar between groups. However, EF fell less over the
8-wk study period in the ACEI- group (
13 ± 11 vs.
22 ± 4% in ACEI, P < 0.05). The ratio of adjacent to remote region
123I-MIBG uptake was greater in
ACEI- animals than in the ACEI group (0.93 ± 0.06 vs. 0.86 ± 0.07, P < 0.04). When added to ACE
inhibition after transmural anteroapical MI, -blockade improves EF
and adjacent regional sympathetic innervation but does not alter LV size.
magnetic resonance imaging; myocardial infarction; remodeling; myocardial contraction
| |
INTRODUCTION |
LEFT VENTRICULAR (LV) remodeling after large myocardial
infarction (MI) (17, 22) is characterized by infarct expansion (3, 4),
lengthening of noninfarcted segments (19), global ventricular
dilatation, and dysfunction in adjacent noninfarcted regions (13).
Angiotensin-converting enzyme inhibition (ACEI) is known to limit LV
remodeling and mortality in animal models (24) and in humans (10, 23,
28, 30). -Blockade has known benefits in limiting mortality after MI
(2, 5, 20), and retrospective analyses from two large clinical trials
of ACEI in the presence of LV dysfunction after large MI (26, 32) have
demonstrated the mortality benefits of the combination of -blockade
and ACE inhibition in this setting. However, the effect of -blockade
on LV remodeling post-MI is variable and dependent on the animal model,
-blocker used, and dosing (6, 9, 21), and the mechanisms underlying
the additional benefit are incompletely understood.
We have previously demonstrated reduced sympathetic innervation in
association with mechanical dysfunction in normally perfused noninfarcted regions adjacent to transmural anteroapical infarction using magnetic resonance tagging at 8 wk post-MI in an ovine model (14). We have also shown that ACEI limits this mechanical dysfunction in conjunction with its limitation of global LV remodeling in this
model (12). We hypothesized that -blockade added to ACEI during LV
remodeling after MI would preserve regional function and sympathetic
innervation in adjacent noninfarcted regions and further limit LV remodeling.
| |
METHODS |
Seventeen female Dorsett sheep were studied. All underwent magnetic
resonance imaging (MRI) before MI (see protocol below). Left
thoracotomy was performed as previously described (12-15) with
ligation of the left anterior descending coronary artery and its second
diagonal branch to create a moderate-sized transmural anteroapical
infarction. On day 2 post-MI, animals
were randomized to ramipril (10 mg once/day) (ACEI,
n = 8) or to combination therapy with
ramipril (10 mg once/day) and metoprolol (50 mg twice/day) (ACEI-,
n = 9). The dose of ramipril is one
that has been demonstrated to limit LV remodeling in this model in
previous studies (12). The dose of metoprolol was chosen as a dose that
reduced resting heart rate by 30 beats/min in normal animals. Heart
rate and blood pressure, by automated pediatric cuff in the left
forelock of the standing animal, were measured at weekly intervals.
Repeat MRI was performed 8 wk later.
MRI.
The anesthetized, ventilated animal was placed in the right lateral
decubitus position on a phased array surface coil in a Siemens 1.5T
scanner, and electrocardiographic gating was initiated. Intravenous 5%
guafenesin and 500 mg of ketamine provided heavy sedation
during imaging. Localizing scout images were performed followed by
breath hold, segmented k-space, and multiphase gradient echo cine
series [for measurement of LV mass, volumes, and ejection fraction (EF)] spanning the LV from apex to base (Fig.
1A).
Imaging parameters were repetition time (TR) of 60 ms (with
view-sharing, yielding a 30-ms temporal resolution), echo time (TE) of
4.8 ms, slice thickness of 7 mm, 128 × 256 matrix, and 25-cm
field of view producing a final interpolated pixel size of 0.95 mm2. For analysis of regional
intramyocardial function, short-axis breath hold, segmented k-space,
and multiphase gradient echo-tagged images (1, 36) were obtained
spanning the LV from apex to base (Fig.
1B). Imaging parameters included
7-mm thick images, 7-mm tag stripe separation, TR of 70 ms (with view
sharing, yielding a 35-ms temporal resolution), TE of 4 ms, 128 × 256 matrix, 25-cm field of view, final interpolated pixel size of 0.95 mm2, and two signal averages.
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Fig. 1.
A: apical short-axis end-systolic cine
image in an animal treated with angiotensin-converting enzyme inhibitor
plus -blocker therapy at 8 wk after infarction. Thinned transmurally
infarcted septum can be seen from 1 o'clock to 5 o'clock in this
image. Right ventricular apex can also be seen from 1 o'clock to 5 o'clock in image. B: tagged magnetic
resonance apical short-axis image at end systole from same animal at
same location as in A at 8 wk post-MI.
Thinned infarcted anteroseptum can be seen from 1 o'clock to 5 o'clock in image.
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123I-labeled
m-iodobenzylguanidine uptake.
m-Iodobenzylguanidine (MIBG) was
labeled with 123I with methods as
previously described (14, 33). At 8 wk postinfarction after repeat MRI,
the thorax was opened, and left atrium and descending aorta were
cannulated. All animals were infused with two different sets of
fluorescent latex microspheres (3 × 106, 15 µm in diameter), one
before and one during adenosine infusion (0.14 mg · kg
1 · min1).
Blood samples were withdrawn for a total of 3 min (1 min before and 1.5 min after a 30-s injection of microspheres) at a constant rate (5 ml/min) from the descending aorta for control measurement of
fluorescence. One hour before death, sheep were injected with 1.4 ± 0.1 mCi 123I-MIBG. After 60 min,
the heart was excised and cut in 1-cm-thick slices. The sharply defined
infarct borders were identified; tissue within 2 cm of the transmural
infarct was termed adjacent, and tissue beyond 2 cm was termed remote
as previously defined (12-15). Infarcted tissue was weighed and
percent infarct calculated as infarct weight per total LV weight.
Slices were further sectioned into 1- to 2-g samples with regions
marked and counted on a gamma counter to quantify
123I-MIBG uptake per gram of
tissue. The MIBG myocardial uptake was expressed in counts per gram,
and with the use of the specific activity, absolute molar MIBG uptake
was determined for each piece in adjacent and remote noninfarcted regions.
Microsphere blood flow.
The same 1- to 2-g pieces were digested as previously described (14),
and their fluorescence was determined by an automated fluorescence
spectrophotometer and compared with reference blood samples.
Fluorescence from tissue samples before and after adenosine infusion as
a measure of flow reserve was compared in adjacent and remote
noninfarcted regions.
Image analysis.
LV mass index (LVMI), end-diastolic and end-systolic volume indexes
(EDVI and ESVI, respectively), and EF were measured from stacked
short-axis cine slices by a single observer blinded to therapy (A. L. Shaffer) (see Fig. 1A). Regional
percent intramyocardial segment shortening (%S) was measured from
stacked short-axis tagged images (see Fig.
1B) using a software package (VIDA,
Univ. of Iowa) on a SUN work station by a different blinded observer
(T. M. Theobald) using a previously described methodology (12-15). Interstripe distances were measured at end systole
(Les) and end diastole (Led),
and %S was calculated as %S = 100(Led Les)/Led. %S was measured at endocardial and epicardial sites in segments located within infarcted, adjacent, and remote regions as previously defined.
Statistical analysis.
Changes between baseline and 8 wk post-MI within each treatment group
in heart rate, blood pressure, LVMI, EDVI, ESVI, stroke volume index
(SVI), EF, and regional %S were compared by Student's paired
t-test. Between-group differences in
the change in any of these parameters over the 8-wk study period were
analyzed using two-way ANOVA. Regional differences in blood flow and
blood flow reserve between groups at 8 wk post-MI were compared between
groups by two-way ANOVA. Regional
123I-MIBG uptake within groups was
compared by paired t-test. Because of
differential 123I-MIBG dosing and
uptake in each animal, absolute
123I-MIBG uptake was not compared
between groups. The ratio of adjacent to remote region
123I-MIBG uptake was compared
between groups by unpaired t-test.
| |
RESULTS |
Mean infarct mass as percentage of total LV mass by pathological
analysis at 8 wk after MI was 14 ± 3% in the ACEI- group and 16 ± 4% in the ACEI group (P = NS).
At baseline, heart rate and blood pressure were not different between
groups. As expected, the fall in heart rate over the 8-wk study period
(Table 1) was greater in the ACEI- group
[34 ± 16 (SD) beats/min] than that in the ACEI
animals (9 ± 17 beats/min,
P < 0.006). The change in blood
pressure was similar in both groups (Table 1).
Changes in LVMI, EDVI, SVI, and EF over the 8 wk are shown in Table
2. At baseline, all of these parameters
were similar between groups. The increase in LVMI and LV EDVI and ESVI
was similar in the two groups. However, EF fell less over the 8-wk study period in the ACEI- group (13 ± 11 vs. 22 ± 4% in ACEI, P < 0.05). In
addition, SVI increased in the ACEI- group (0.1 ± 0.3 ml/kg) but fell slightly in the ACEI group (0.1 ± 0.1, P < 0.05).
At baseline, %S in adjacent and remote noninfarcted regions was not
different between groups, and the expected transmural heterogeneity was
noted with subendocardial regions demonstrating greater %S than
subepicardial regions (13, 14) (Table 3). By 8 wk, there was a trend toward better preservation of %S in the
ACEI- group in the adjacent subendocardium (10 ± 2 vs. 8 ± 4% in the ACEI group, P = 0.11), but
the change over the 8-wk period was not different between groups. The
decline in adjacent noninfarcted %S during the remodeling period was
10 ± 3% in ACEI and 8 ± 3% in ACEI-
(P = NS). As expected, no significant
fall in remote noninfarcted %S was seen in either group [0 ± 3%
in ACEI and 1 ± 6% in ACEI-, P = not
significant (NS)].
Blood flow at 8 wk post-MI was not different between groups in adjacent
noninfarcted regions (1.0 ± 0.4 ml · min1 · g1
in ACEI and 1.0 ± 0.3 ml · min1 · g1
in ACEI-). In remote regions, blood flow was not different from adjacent regions and likewise was similar between groups (1.0 ± 0.5 and 0.9 ± 0.3 ml · min1 · g1,
respectively). Blood flow reserve was also similar between groups in
both adjacent and remote noninfarcted regions. In adjacent regions,
blood flow reserve was 2.4 ± 1.0 in ACEI and
2.2 ± 0.9 in ACEI- (P = NS),
and in remote regions, blood flow reserve was 2.6 ± 1.0 in ACEI and
2.2 ± 0.9 in ACEI- (P = NS).
In both groups, quantitative
123I-MIBG uptake was less in
adjacent noninfarcted regions than in remote. In ACEI animals,
123I-MIBG uptake was 0.87 ± 0.37 nmol/g in adjacent regions and 1.03 ± 0.48 nmol/g in remote
regions (P < 0.02). In ACEI-
animals, 123I-MIBG uptake was 0.78 ± 0.31 nmol/g in adjacent regions and 0.85 ± 0.35 nmol/g in
remote (P < 0.02). The ratio of
adjacent to remote region
123I-MIBG uptake was greater in
ACEI- animals than in the ACEI group (0.93 ± 0.06 vs. 0.86 ± 0.07, P < 0.04) (Fig.
2).
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Fig. 2.
Graph demonstrating ratio of
123I-labeled
m-iodobenzylguanidine (MIBG) uptake in
adjacent (Adj) noninfarcted regions compared with remote (Rem)
noninfarcted regions in 2 groups of animals. ACEI,
angiotensin-converting enzyme inhibitor; ACEI+, ACEI plus
-blocker. Ratio is significantly closer to unity in ACEI-
group.
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| |
DISCUSSION |
When added to ACEI after transmural anteroapical MI, -blockade
lowers heart rate and improves EF but does not alter blood pressure, LV
mass, or cavity size. Neither regional blood flow nor flow reserve is
altered. Sympathetic innervation is improved in adjacent noninfarcted
regions, and regional function tends to be better preserved in those
regions. Restored sympathetic innervation in adjacent noninfarcted
regions by -blockade may contribute to improved regional and global
function in the remodeled postinfarct LV. In addition, the improvement
in innervation may reduce the arrhythmias generated from these adjacent
regions, contributing to mortality reduction seen with -blockade
after MI.
Comparison with previous studies.
The lack of additive effect of -blockade on LV end-diastolic or
end-systolic volume is consistent with prior animal studies of
postinfarct remodeling. In rat models of MI, the efficacy of nonselective -blockers in limiting remodeling has been
controversial. Fishbein et al. (6) showed that propranolol therapy in a
rat model of transmural infarction blunted the increase in myocyte hypertrophy yet was associated with increased ventricular dilatation. In a rat model of reperfused nontransmural infarction, propranolol therapy was associated with increased LV cavity area and reduced wall
thickness in infarcted and noninfarcted regions, suggesting pro-remodeling effects (21). Using
1-selective blockade, Hu et al.
(9) have shown that infarct size and timing of the start of therapy
impact on its effect on LV remodeling. Early -blockade (begun 30 min
after infarction) limited mortality, and early or late (14 days
post-MI) -blockade had favorable effects on LV volumes only in the
setting of large infarction.
1-Selective -adrenergic
blockade favorably modulated remodeling in two animal models of
myocardial damage in which it was compared directly with ACEI. Sabbah
et al. (25) used a model of congestive heart failure in the dog induced
by intracoronary microembolizations. They demonstrated that in dogs
treated with enalapril or metoprolol, LV EF did not decrease over time,
and LV end-diastolic and end-systolic volumes did not change, whereas in control animals or digoxin-treated animals, LV volumes increased. McDonald et al. (16) have likewise shown that therapy with either captopril or metoprolol reduced LV mass and end-diastolic volume in a
canine model of chronic LV remodeling from previous transmyocardial direct current shock-induced myocardial damage. To our knowledge, investigators have not previously studied the additive effects of ACEI
and -blockade on LV remodeling in animal models.
-Blockade alone has been shown to reduce late mortality and
reinfarction in large clinical trials in MI in humans (2, 5, 20, 35).
Recently, investigators from the SAVE study have demonstrated the
additive beneficial effects of -blockers to ACE inhibitors (32).
Once adjustments were made for baseline variables, the addition of
-blockers in these patients with anterior MI and asymptomatic LV
dysfunction was associated with a 30% risk reduction in cardiovascular
death and a 21% risk reduction for development of heart failure.
Role of sympathetic innervation.
We have previously demonstrated partial sympathetic denervation in the
remodeled LV that parallels regional dysfunction (14) in adjacent
noninfarcted regions. The present study demonstrates that -blockade
is associated with a relative increase of
123I-MIBG uptake in adjacent
noninfarcted regions. The reduction of sympathetic innervation (14%)
is halved by the addition of -blockade (7%). Blockade of
circulating and local catecholamines may hasten reinnervation in
previously denervated tissue.
123I-MIBG uptake has been
demonstrated to increase in adjacent noninfarcted regions during more
chronic periods after MI in humans (from 3 to 12 mo post-MI) (7), but
the influence of -blockade on this process has not been examined.
In the adjacent noninfarcted subendocardium, regional function (%S)
tended to be higher in the -blocked animals, consistent with the
hypothesis that improved sympathetic innervation is associated with
improved regional function. With -blockade, sympathetic innervation
improved to a much greater extent (by ~50%) than did regional %S,
which improved by only 20% (from 8% in the ACEI group to 10% in the
ACEI- group). A previous study demonstrated that the extent of
dysfunction is greater than the extent of denervation (14). Other
mechanisms such as local cellular hypertrophy (15) and intrinsic
myocyte dysfunction undoubtedly contribute to the dysfunction. The
addition of -blockade may not impact enough on cellular hypertrophy
and intrinsic myocyte dysfunction to improve adjacent regional function.
Other benefits beyond effects on systolic performance may result from
the reinnervation in adjacent noninfarcted regions associated with
-blockade. These regions are associated with spontaneous ventricular
tachyarrhythmias in humans after MI (27) and demonstrate supersensitivity of refractory period shortening to adrenergic stimulation by norepinephrine (18). Therefore, denervation in these
regions is likely to contribute to the genesis of ventricular arrhythmias that are a major cause of mortality after large MI. Reinnervation with the addition of -blockade, as demonstrated in the
present study, may reduce the inducibility of ventricular arrhythmias
and contribute to the reduction in sudden death and total mortality
seen in large trials of -blockers after MI (2, 20). The reduction in
sudden death and mortality is greatest in those patients with a history
of heart failure and/or enlarged heart size (31).
Limitations.
No group of animals was studied with -blockade alone. However, ACE
inhibitors are likely to be background therapy for all patients with LV
dysfunction after anterior MI based on previous large clinical trials
(10, 23, 30), and relevant questions remain regarding the role of
additive -blockade in these patients. The two groups studied were
limited in size. However, despite the small
n, significant intergroup differences
were found in regional sympathetic innervation and global systolic
function. Only one time point in the course of postinfarct remodeling
was studied. The 8-wk time point post-MI was chosen because of the extent of remodeling that occurs and because of our previous experience using 123I-MIBG at this time point
in this model in untreated postinfarct animals (14).
The difference in EF between the groups was greater than the difference
found in regional function as measured by %S. %S is only one
direction of measured strain within the myocardium, namely, circumferential, and EF is a measure of the result of myocardial deformation in three dimensions. The trend to improved adjacent subendocardial function in the ACEI- group was in the same direction as the differences in global function.
123I-MIBG uptake was expressed as
regional ratios within animals. The absolute value of
123I-MIBG uptake could not be
compared directly between animals or groups because of expected
differences in 123I-MIBG labeling
before infusion in each animal. Changes in nonneuronal uptake of
123I-MIBG may account in part for
reduced 123I-MIBG uptake in
noninfarcted tissues (29), although most reductions in nonneuronal
uptake have been demonstrated within nonviable infarcted myocardium. In
addition to changes in presynaptic sympathetic nervous system function
in the post-MI setting, significant changes may occur in the cascade of
postsynaptic events (11). ACEI has been demonstrated to upregulate
-adrenergic receptors (34), which also occurs with -blockade (8).
The combination of ACEI and -blockade would therefore be expected to
further enhance -receptor responsiveness. Postsynaptic events will
be a direction for future investigation in this model.
| |
ACKNOWLEDGEMENTS |
We gratefully acknowledge the technical and analytical support of
Amy L. Shaffer and Therese M. Theobald.
| |
FOOTNOTES |
This study was supported by American Heart Association, National
Office, Grant-in-Aid 96014830.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: C. M. Kramer,
Univ. of Virginia Health Systems, Departments of Radiology and
Medicine, Box 170, Charlottesville, VA22908.
Received 5 February 1999; accepted in final form 28 May 1999.
| |
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