(Circulation. 1995;91:802-812.)
© 1995 American Heart Association, Inc.
Articles |
Effect of Enalapril on Ventricular Remodeling and Function During Healing After Anterior Myocardial Infarction in the Dog
From the Cardiology Division of the Department of Medicine, University of Alberta, and University of Alberta Hospital, Edmonton, Canada.
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Abstract |
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Background Ventricular remodeling after myocardial infarction involves changes in ventricular size, shape, structure, and matrix that impact on function. Prolonged angiotensin-converting enzyme inhibition after infarction with captopril reduces ventricular enlargement and improves clinical outcome, but whether enalapril produces similar benefits is controversial.
Methods and Results The effect of enalapril during healing between 1 day and 6 weeks after myocardial infarction on in vivo changes in ventricular size, shape, mass, and function (asynergy, or akinesis and dyskinesis, and ejection fraction), as determined by serial two-dimensional echocardiography, hemodynamics, postmortem topography (planimetered short- and long-axis ventricular contours), and collagen content (determined by levels of hydroxyproline, a marker for collagen), was measured in 25 instrumented dogs. The dogs were randomized 1 day after left anterior descending coronary artery ligation to a control group (no treatment) and a group receiving oral enalapril (2.5 mg BID). Compared with no treatment, enalapril produced a sustained lowering of left atrial pressure but no difference in heart rate and mean blood pressure over the 6 weeks. Also compared with no treatment, enalapril modified in vivo remodeling parameters between 1 day and 6 weeks, with less elongation of the asynergy-containing segment, a lower expansion index (ratio of endocardial lengths of infarct to non–infarct-containing segments demarcated by papillary muscle landmarks), less scar wall thinning, a lower thinning ratio (ratio of average thickness of infarcted wall to average thickness of the normal wall), smaller ventricular volume, less regional bulging and aneurysm frequency, prevention of the increase in ventricular mass, less total extent of asynergy, and higher volume ejection fraction. At postmortem examination, scar mass was similar in the two groups, but topographic maps with enalapril revealed less infarct bulging, flatter infarct scars, and less noninfarct wall thickness. In addition, postmortem collagen content was similar in noninfarct zones of the two groups but lower in infarct zones of the dogs given enalapril.
Conclusions Prolonged enalapril therapy, in a dose that did not lower blood pressure, during healing after anterior infarction produced prolonged reduction of left ventricular preload in dogs. This diastolic unloading was associated with limitation of remodeling parameters (infarct expansion and thinning, progressive ventricular dilation and hypertrophy, and regional bulging), less total asynergy, and improved left ventricular ejection fraction. Although angiotensin-converting enzyme inhibition was associated with lower collagen content in the infarct area and altered scar topography, these effects did not impact negatively on overall remodeling and function.
Key Words: myocardial infarction • ventricles
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Introduction |
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Postinfarction ventricular remodeling is a complex process involving changes in ventricular size, shape, structure, and the supporting collagen matrix.1 2 These changes during remodeling progress during infarction, postinfarction healing, and beyond.2 3 4 The changes are especially marked after anterior myocardial infarction and tend to impact negatively on function and outcome.2 3 5 The angiotensin-converting enzyme (ACE) inhibitor captopril has been shown to prevent progressive ventricular dilation and functional deterioration after anterior infarction in rats,6 dogs,7 8 and humans9 and to improve survival in humans.10 The ACE inhibitor enalapril has been shown to delay progressive ventricular dilation and preserve function in the SOLVD prevention trial of left ventricular dysfunction in patients with remote infarction, ischemic cardiomyopathy, and dilated cardiomyopathy.11 However, in the CONSENSUS II study there was increased mortality in patients with infarction,12 and in the SOLVD treatment trial progressive ventricular dilation continued despite stable ejection fraction in patients with severe dysfunction.13 No detailed animal studies of the effects of enalapril during healing after anterior infarction have been reported.
The purpose of this study was to determine the effect of prolonged ventricular unloading with enalapril therapy, in a dose that did not lower blood pressure and was administered during the subsequent healing process in the dog after completion of anterior myocardial infarction, on (1) in vivo changes in left ventricular size, shape, mass, and function using quantitative two-dimensional echocardiography7 8 and (2) postmortem topography and collagen matrix.1 7 8
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Methods |
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Experiments were approved by the institutional animal welfare committee and conformed to the guiding principles of the American Physiological Society.
Experimental Preparation
Thirty-eight healthy mongrel dogs
(16 to 29 kg) of both sexes
were instrumented as described previously7 8 through
a
left lateral thoracotomy under general anesthesia (sodium
pentobarbital, 30 mg/kg IV) with polyethylene catheters in the external
jugular vein, internal carotid artery, and left atrium. A silk ligature
was placed around the middle of the left anterior descending coronary
artery, just below the first diagonal branch, and tied. To ensure
consistent echocardiographic orientation for serial topography, metal
beads were sutured on the anterior, lateral, and posterior epicardial
surfaces in the short-axis plane at the mid–left ventricular level.
After the pericardium and chest were closed, penicillin (1 million U)
and streptomycin (1 g) were given intramuscularly and the dogs were
returned to their cages.
Experimental Design
One day after occlusion, the 34 surviving
dogs were randomized
to a control group (25 mL water) or a group receiving enalapril (2.5-mg
tablet with 25 mL water BID) for 6 weeks. The dogs had free access to
fluids, and no attempt was made to treat heart failure. At 6 weeks, the
25 surviving dogs were anesthetized and the hearts were arrested in
diastole with an overdose of intravenous potassium chloride, excised,
washed in normal saline solution, and weighed.
Measurements During Healing
As described
previously,7 8 serial two-dimensional
echocardiograms (Toshiba SSH-65A, 3.5-MHz transducer), ECGs (Gould),
and hemodynamics (Statham P23Db for left atrial and arterial pressures)
were recorded, with the dogs standing in a sling for support, at eight
intervals in the conscious state: at baseline (before surgery,
occlusion, and therapy), 2 days postocclusion, weekly during
therapy for 5 weeks, and finally 24 to 48 hours after therapy was
stopped at 6 weeks. Hemodynamics and ECGs were also recorded in the
anesthetized animals before and after surgery. Echocardiograms were
recorded in standard views7 8 (parasternal long-axis;
five
parasternal short-axis from base to apex at mitral, chordal,
midpapillary, low papillary, and apical levels; and apical four- and
two-chamber) and stored on 0.5-in VHS videotape. Blood gases,
hemograms, and serum electrolytes were monitored. Venous plasma renin
and aldosterone levels were measured in the first 18 dogs
(preoperatively and at 2 and 6 weeks) by
radioimmunoassay.14
Postmortem Measurement of Scar Size, Geometry, and Collagen
As described previously,7 8 15
the anatomic risk
region was measured on postmortem coronary arteriograms made using
simultaneous pressure-controlled injections of all coronary arteries of
fresh hearts with a mixture of barium sulfate and gelatin, followed by
fixation (10% phosphate-buffered formalin solution for 48 hours) of
the hearts in distension (15-cm pressure head), to preserve diastolic
proportions, and radiography of the whole heart (in two perpendicular
planes) and transverse sections (five sections equally spaced, 1 to 1.5
cm thick). Boundaries of the risk region were marked on section
radiographs by consensus of two observers. Left ventricular rings were
weighed and outlines of the rings, occluded zones, and infarct scars
were made on plastic overlays. Infarct size and topographic parameters,
including the thinning ratio (ratio of average thickness of infarcted
wall to average thickness of the normal wall) and expansion index
(ratio of endocardial lengths of infarct to non–infarct-containing
segments demarcated by papillary muscle landmarks), were measured by
computerized planimetry (Hewlett Packard 9835A computer and 9874A
digitizer interfaced with a VAX 750 computer), and average short-axis
topographic maps of each ventricular ring for each group were derived
from the digitized data.7 8 15 Contours
of the left
ventricular epicardium and endocardium made from the whole-heart
radiographs were digitized to map topography and measure the area and
depth of the apical bulge in the long axis, and average long-axis maps
were then constructed for each group.8 15
Histopathology
was done on a 5-mm slice from the ring in the middle of the infarct
zone, and triplicate 5-µm sections were stained with hematoxylin and
eosin, Mallory's stain, or Masson's trichrome, respectively, and
examined for infarction and collagen content.1 Myocardial
hydroxyproline (expressed as mg/g dry tissue weight), a marker for
collagen, was measured in transmural samples (100 to 200 mg) taken from
the center and border regions of the infarct scar and center of the
nonoccluded bed.1
Analysis of Echocardiograms
As described
previously,5 7 8 15 16
coded
echocardiograms were analyzed double-blind on video playback by two
independent observers (B.I.J. and M.I.K.) for in vivo functional and
topographic parameters. Endocardial and epicardial outlines of the left
ventricular images at end diastole and end systole were traced with a
light pen (Diasonics CardioRevue Center) and copied on plastic
overlays. Anatomic landmarks, such as papillary muscles and junctions
of right and left ventricles, were noted on the tracings. Markings of
asynergy, defined as akinesis (no systolic inward motion and no
thickening), dyskinesis (systolic outward motion and thinning), or
both, were made on each endocardial diastolic outline by careful visual
assessment of motion and thickening during repeated video playbacks.
The circumferential extents on each short-axis view were then digitized
(Hewlett Packard 9878A and 9835A) and used to compute the total
endocardial surface area of asynergy. Outlines from five short-axis and
two long-axis views were used to compute volumes by means of the
modified Simpson's rule. Global ejection fraction was calculated
([end-diastolic volume–end-systolic volume] divided by
[end-diastolic volume]). The interobserver error was less than 5% in
marking asynergy, segment length, wall thickness, and areas of
outlines, in agreement with previous
studies.5 7 8 15 16
For the postmortem hearts, topographic measurements were made on
end-diastolic outlines of short-axis images at the
papillary level, and the expansion index (ratio of the lengths of the
asynergy-containing and the non–asynergy-containing segments),
thinning ratio (ratio of the average thicknesses of the asynergic and
non-asynergic zones), and regional area ejection fraction
([end-diastolic area–end-systolic area] divided by
[end-diastolic
area]) were computed. The degree of regional bulging (distortion) in
the asynergic zone was characterized by its area and depth and the peak
distortion index, as described
previously.5 7 8 17 Left
ventricular aneurysm was defined as the presence of diastolic bulge
with further bulging and thinning in systole. Left ventricular mass was
calculated from the volume of myocardium (difference in volumes of
epicardial and endocardial shells at end diastole) multiplied by an
assumed specific gravity of 1.05 g/mL.
Statistics
Data were analyzed in blinded fashion. The
statistical
tests used were ANOVA for the significance of difference within and
between groups, 2x2 
2 test for the significance of
difference in event frequency between groups, and repeated-measures
ANOVA for comparing serial data within groups. Results are
presented as mean±SEM. Statistical significance was set at
P<.05.
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Results |
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Of the 34 dogs that were randomized 24 hours postocclusion, 25 survived 6 weeks and were killed according to the protocol. Data from 9 of the 34 dogs (26%) that died in their cages, presumably from arrhythmias, congestive heart failure, or both and mostly between 1 and 12 days, were excluded from analysis (5 in the enalapril group and 4 in the control group). The infarcts in those dogs were moderate in size (20.2% to 26.2% of left ventricle and 82% to 86% of risk region). Detailed analysis of the data from the 25 dogs that survived the 6 weeks (12 in the enalapril group and 13 in the control group) forms the basis of this report.
Hemodynamic Effects
Enalapril produced a marked decrease in
the mean left
atrial pressure, very little change in mean arterial pressure, and no
change in heart rate over the 6 weeks (Table 1
). Thus,
heart rates in the two groups were similar at baseline, and the
increases postocclusion and decreases between 1 and 6 weeks were also
similar. Mean arterial pressures in the two groups were similar at
baseline and did not differ significantly over the 6 weeks, the percent
change over baseline by 6 weeks being the same in the enalapril and
control groups (-2% in both groups). In contrast, mean left atrial
pressures in the two groups were comparable at baseline and increased
similarly postocclusion but were lower in the enalapril group than in
the control group over the subsequent 6 weeks, the respective values
being 12 versus 17 mm Hg at 2 days (P<.05) and 7 versus 13
mm Hg at 6 weeks (P<.01). The calculated double product
(defined as heart rate multiplied by mean blood pressure [beats per
minutexmm Hgx102]) did not differ significantly
(P=NS) between the control and enalapril groups over the 6
weeks, mean values being 128 versus 134 at baseline and 118 versus 117
at 6 weeks, respectively, and the percent change over the 6 weeks being
-28±5% in the control group versus -26±6% in the
enalapril group.
However, a calculated triple product (defined as heart ratexmean blood
pressurexmean left atrial pressure [bpmxmm
Hg2x103]) was similar in the two groups at
baseline (77 in the control group versus 107 in the enalapril group,
P=NS) but was greater in the control group than in the
enalapril group at 2 days (273±25 versus 183±32, respectively,
P<.05) and until the 6 weeks, the respective values at 6
weeks being 147 versus 86 (P<.05). Thus, the percent change
in triple product over the 6 weeks was less with enalapril
(-13±29%
in the enalapril group versus 74±27% in the control group,
P<.05).
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In Vivo Changes in Infarct and Ventricular Stretch
Enalapril
prevented the elongation of infarcted and noninfarcted
segments seen over 6 weeks in the control group (Fig 1).
It should be noted that echocardiographic data shown for the 6-week
point in Fig 1, as well as in Figs 2 through
5, are those
obtained 24
to 48 hours after therapy had stopped. At baseline, the
infarct-containing anterior segment lengths (7.8 cm in the control
group versus 8.1 cm in the enalapril group), posterior segment lengths
(4.3 versus 4.3), and expansion indexes (1.84 versus 1.88) were similar
(P=NS) in the two groups. However, between 2 days and 6
weeks the anterior segment was persistently shorter in the enalapril
group than in the control group (P<.005), the percent
changes from baseline being, respectively, 0.1±4.1% versus
27.3±3.7% at 2 days (P<.001) and 9.1±3.6% versus
56.9±14.4% at 6 weeks (P<.01). Enalapril also prevented
elongation of the noninfarcted posterior segment, the respective
percent changes in lengths from baseline for the two groups being
-6.6±3.9% versus 2.1±0.9% at 2 days (P<.05)
and
-1.6±3.8% versus 9.7±2.5% at 6 weeks (P<.05).
The
expansion index was also significantly less in the enalapril group than
in the control group (P<.01).
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In Vivo Changes in Infarct and Ventricular Wall Thickness
Compared with the control group, enalapril reduced infarct
thinning beyond 1 week but did not influence the increase in noninfarct
wall thickness significantly until 6 weeks (Fig 2
).
Thus, at baseline, thicknesses of anterior (0.95 cm in the enalapril
group versus 0.97 cm in the control group) and posterior (0.95 and 0.98
cm, respectively) walls were similar (P=NS). However,
compared with the control group, the percent change in anterior wall
thickness over baseline was less with enalapril at 1 week (-22% in
the enalapril group versus -36% in the control group,
P<.05) and 6 weeks (-27% versus -44%, respectively,
P<.01). In contrast, the percent changes in posterior wall
thickness in the two groups were similar at 2 days (-4.1% versus
2.3%, respectively, P=NS) but slightly less with enalapril
at 2 weeks (2.8% versus -6.9%, P<.05) and 6 weeks
(-4.3% versus 7.1%, P<.005). Moreover, the thinning
ratio was significantly greater (P<.01) in the enalapril
group than in the control group over the 6 weeks.
In Vivo Changes in Regional Bulging
Enalapril decreased the
degree of regional bulging of the
asynergic infarct zone in the anterior segments (Fig 3).
The values of peak distortion, area of distortion, and depth of
distortion were zero at baseline, increased after occlusion, and
continued to increase over the 6 weeks in the control group. In
contrast, these indexes were less for the enalapril group than for the
control group at 2 days and through the 6 weeks. The data for peak
distortion and area of distortion are depicted in Fig 3. In
addition,
the frequency of ventricular aneurysms was less in the enalapril group
than in the control group at day 2 (8 of 12 versus 13 of 13,
respectively; 2=2.98, P<.05) through
the 6 weeks (5 of 12 versus 13 of 13, 2=7.84,
P<.005).
In Vivo Changes in Ventricular Dilation
In the treatment
group, enalapril limited the progressive
ventricular dilation that was seen in the control group (Fig
4). The ventricular volumes in the enalapril and control
groups were similar at baseline for end diastole (53.8 versus 49.9 mL,
respectively) and end systole (19.1 versus 18.1 mL). However, the
percent changes in diastolic volume were less in the enalapril group
than in the control group between 2 days and 6 weeks, the respective
values being -10±5% versus 45±10% at 2 days
(P<.001)
and 15±6% versus 87±13% at 6 weeks (P<.001). The
percent changes in systolic volume over that interval were also less in
the enalapril group than in the control group, the respective values
being 40±13% versus 132±27% at 2 days (P<.01) and
63±14% versus 151±19% at 6 weeks (P<.005).
In Vivo Changes in Regional and Global Ventricular Function
Enalapril decreased the extent of regional mechanical dysfunction
and improved global systolic function between 2 days and 6 weeks
compared with no treatment (Fig 5). There was no
asynergy in either group at baseline. However, circumferential left
ventricular asynergy at the papillary level was significantly less
(P
.05) with enalapril after 1 week, the values being
21±2% in the enalapril group versus 28±2% in the control group
at 1
week and 18±1% versus 23±2%, respectively, at 6 weeks. Global
left
ventricular asynergy was significantly less (P.05) with
enalapril after 2 weeks, the respective values being 12% versus 15%
at 2 weeks and 12% versus 14% at 6 weeks. Area ejection fractions at
the papillary level were similar in the two groups at baseline (57.9%
in the enalapril group versus 55.7% in the control group,
P=NS) but slightly greater with enalapril than with no
treatment between 2 days and 6 weeks (P.05), the values
being 37.3% in the enalapril group versus 30.4% in the control group
at 2 days (P<.025) and 39.8% versus 32.9%, respectively,
at 6 weeks (P<.05). Volume ejection fraction also improved
in the enalapril group compared with the control group, the values
being 67% in the enalapril group versus 64% in the control group at
baseline (P=NS), 50% versus 44% at 2 days
(P<.05), and 53% versus 47% at 6 weeks
(P<.05).
In Vivo Changes in Left Ventricular Mass
Left ventricular
mass was slightly greater in the enalapril group
than in the control group at baseline (104±8 versus 89±7 g,
respectively, P=NS) but was slightly less than in the
control group at 6 weeks (100±8 versus 92±5 g,
P=NS).
Although postmortem left ventricular masses in the formalin-fixed
hearts at 6 weeks were similar in the two groups (80 versus 84 g,
respectively) and correlated with the in vivo mass at 6 weeks
(r=.8, P<.001), they were systematically
overestimated on the echocardiograms. However, over the 6 weeks, in
vivo ventricular mass increased in the control group but decreased
slightly in the enalapril group (Fig 6). Thus, the
percent change was less in the enalapril group than in the control
group at 1 week (-0.3% versus 8.9%, respectively, P<.1)
and at 6 weeks (-8.2% versus 14.6%, P<.005).
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Effect on Arrhythmias and Thrombus
The frequency of
ventricular premature beats on electrocardiograms
did not differ significantly between the enalapril and control groups
at 2 days (5 of 12 versus 8 of 13, respectively;
2=0.84,
P=NS) or 6 weeks (3 of 12 versus 7 of 13;
2=0.42, P=NS). The frequency of left
ventricular thrombus on echocardiograms was also not significantly
different in the two groups at 2 days (2 of 12 versus 5 of 13,
respectively; 2=0.46, P=NS) or 6 weeks
(2 of
12 versus 4 of 13; 2=1.79, P=NS).
Effect on Neurohumoral Profile
Renin and aldosterone levels
were measured in 15 of the 25 dogs (8
controls, 7 enalapril) and confirmed ACE inhibition.7
Venous plasma levels of renin (0.86±0.14
ng · mL-1 · h-1 in the
enalapril
group versus 0.76±0.14
ng · mL-1 · h-1 in the control
group)
and aldosterone (123±26 versus 126±31 pmol/L, respectively) were
similar in the two groups at the preoperative baseline
(P=NS). However, at 6 weeks, the enalapril group had higher
plasma renin compared with the control group (3.06±0.72 versus
1.51±0.32
ng · mL-1 · h-1,
respectively, P<.05) and slightly lower aldosterone (39±28
versus 107±39 pmol/L, respectively, P<.1).
Postmortem Scar Size
The mass of the infarct scar at 6 weeks
was similar
(P=NS) in the enalapril and control groups, in weight
(4.1±0.6 versus 5.1±0.7 g, respectively) as percent of the left
ventricle (5.1±0.7% versus 6.4±0.8%), and as percent of the risk
region (39.4±5.6% versus 46.1±5.1%). The masses of the left
ventricle (82.5 versus 79.6 g) and risk region (11.0 versus 11.2 g)
were also similar in the two groups. No differences in scar tissue were
detected on standard histology between the two groups at 6 weeks.
Collagen Content
Regional collagen content (Fig
7) was similar in
the noninfarcted posterior ventricular wall of the enalapril and
control groups (4.53±0.28 versus 4.46±0.33 mg hydroxyproline per
g,
respectively, P=NS) but significantly less in the infarct
center (19.42±4.37 versus 44.91±4.11 mg/g, P<.001)
and
infarct border (4.81±0.32 versus 18.28±5.11 mg/g,
P<.025)
regions of the anterior wall in the enalapril group.
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Effect on Postmortem Ventricular and Scar Topography
Computer-generated average maps of planimetered short-axis
sections of the hearts fixed after diastolic arrest indicated several
differences in remodeling parameters between the enalapril and control
groups (Fig 8A and Table 2). Thus, for
the middle of the risk region (ring 4), the enalapril group showed less
ventricular dilation, reflected in smaller cavity area; less infarct
wall thinning, reflected in similar scar wall thickness; and less
reactive hypertrophy, reflected in a lesser noninfarct wall thickness.
Although the scar areas and mass were similar, the transmural extent of
the scar was less (eg, ring 4: 40% versus 60%, P<.01) and
the angular extents were slightly greater (eg, ring 4: 170° versus
112°, P<.001), indicating altered scar topography with a
flattening of the scar.
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Computer-generated average ventricular contours
in the long axis,
obtained from radiographs of the hearts fixed after diastolic arrest,
showed less apical bulging and cavity dilation in the enalapril group
than in the control group (Fig 8B and Table 2).
Comparing the average
endocardial contours of enalapril and control groups, the bulge had
less depth in the enalapril group than in the control group (2.2 versus
7.1 mm, respectively, P<.005); less area of distortion (0.3
versus 1 cm2, P<.005); and a smaller base (6.7
versus 12.8 mm, P<.01). In addition, scar wall thickness
was greater in the enalapril group than in the control group (6.5
versus 3.1 mm, respectively, P<.001) and cavity area was
less (10.8 versus 12.8 cm2, P<.05).
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Discussion |
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There were three new findings in this study. First, long-term enalapril therapy during healing after anterior myocardial infarction in a well-defined canine model limited left ventricular remodeling and preserved function. Second, these beneficial effects were associated with a dose of enalapril that produced a sustained decrease in left atrial pressure (an index of preload) but no significant decrease in arterial pressure (an index of afterload) over 6 weeks. There were no changes in heart rate or rate-pressure product, but the triple product of heart rate, blood pressure, and mean left atrial pressure (an index of hemodynamic load) decreased. Third, long-term enalapril in the dose administered was associated with a decrease in the collagen content of the infarct scar at 6 weeks despite overall benefits in ventricular remodeling and function. Thus, healing over the first 6 weeks postinfarction in the control group was associated with progressive infarct stretching and thinning, progressive global left ventricular dilation, persistent left ventricular dysfunction, progressive increase in left ventricular mass, and apical bulging with aneurysm formation. In contrast, enalapril (2.5 mg BID) begun 24 hours after infarction and continued for 6 weeks limited further infarct stretching and thinning as well as ventricular enlargement; it also improved regional and global systolic ventricular function, decreased left ventricular mass, and decreased apical bulging and aneurysm frequency.
Merits and Limitations of the Model
During the last decade,
mainly because of the use of thrombolysis,
especially in patients with developed collaterals, the number of
survivors of acute infarction with nontransmural infarcts similar to
those in the dog model has increased. The dog model in this study
produces infarcts that are about 20% of the left ventricle 1 day after
coronary artery occlusion (moderate size) and shrink to about 10% of
the left ventricle by 6 weeks because of scar contraction and
compaction.1 7 8 15 18 19 20
In dogs that died prematurely
between 1 and 12 days after ligation, the infarct measured 20.2% to
26.2% of the left ventricle, while in dogs that were killed at 6 weeks
the scar measured 6% of the left ventricle. The average transmural
extent in the control group was 58% of the scar wall thickness on
morphometric analysis, consistent with collateral protection during
infarction and possibly during healing over the 6 weeks. Moreover, the
control group showed significant ventricular remodeling with regional
and global ventricular dysfunction (eg, 25% of akinesis and dyskinesis
and ejection fraction of 44% at 2 days) and cavity dilation on early
echocardiograms, as well as evidence of infarct expansion, infarct
thinning, ventricular aneurysm, noninfarct zone hypertrophy and
expansion, and cavity enlargement on echocardiograms at 6 weeks.
Quantitative two-dimensional echocardiography was used for measuring in
vivo changes in ventricular topography and function; we took a careful
approach in obtaining systematic tomographic images for subsequent
three-dimensional reconstruction as done
previously.5 7 8 15 16 17
Echo-opaque epicardial beads were
used for consistent serial imaging, and only images obtained while the
dogs were in the conscious state were compared. Postmortem measurements
of remodeling parameters at 6 weeks were made on hearts arrested in
diastole and fixed under equal distending pressure.
Mechanisms
The mechanisms for the beneficial effect of ACE
inhibition on
remodeling during healing after infarction are
complex.2 3 7 8 Five
potential mechanisms were likely
involved: (1) improvement of hemodynamics by means of left ventricular
unloading and decreased wall stress secondary to venous and arterial
dilation; (2) improvement in nutrient collateral blood flow; (3)
reduction of ischemic or reperfusion injury or both and of infarct
size; (4) reduction in circulating ACE activity and cardiotoxic
neurohormones; and (5) reduction in activity of tissue ACE and myocyte
and fibroblast growth factors. The findings in this study underscore
the importance of left ventricular diastolic unloading, decreased
diastolic wall stress, and tissue ACE inhibition. Although benefits
with captopril in previous studies7 8 were associated
with
a 12% to 18% decrease in mean arterial pressure compared with
baseline, in this study enalapril produced similar benefits without a
significant decrease in that parameter. The sequence of
enalapril-induced reduction in preload with little reduction in
afterload and decreased chamber size, diastolic wall stress (Laplace's
law), regional and global mechanical deformation forces, regional
bulging, global dilation, and reactive hypertrophy indicates that the
hemodynamic mechanism played an important role. Findings of increased
left ventricular wall thickness and mass by 1 week and further increase
by 6 weeks in the control group support the paradigm of increased wall
stress, increased wall stretch, and promotion of ventricular
hypertrophy with upregulation of contractile and noncontractile protein
gene expression,21 22 while findings with enalapril
support the reverse paradigm of decreased wall stress, decreased wall
stretch, and prevention of ventricular hypertrophy. Greater regional
hypertrophy in the spared epicardial rim and bordering normal
myocardium of the control group, a response to the greater regional
wall stress associated with the greater bulge and curvature
differences, might explain the lack of difference in infarct scar wall
thickness of some short-axis sections compared with the enalapril
group.
Enalapril might have improved nutrient collateral flow during healing by means of inhibition of bradykininase activity (which would lead to increased levels of bradykinin, prostaglandins,23 and prostacyclin; bradykinin-induced release of nitric oxide24 ), direct vasodilation of coronary as well as venous vessels and arterial beds, and decreased endocardial compression secondary to diastolic unloading. Combined effects of decreased wall stress and increased collateral flow to border zone myocardium (which is usually under greater stress20 ) might preserve nutrient flow and protect the extracellular collagen matrix in the epicardial and lateral bordering myocardium of the risk region. However, potential benefit from a decrease in ischemic injury was not involved because enalapril was begun after completion of infarction.
ACE inhibition in this study was confirmed by the lower aldosterone and higher renin levels in the enalapril group compared with the control group, as found previously with captopril.7 However, activation of the serum renin-angiotensin system (RAS) was not marked in our postinfarction model with compensated heart failure, probably because of an increase in atrial natriuretic peptide, which lowers aldosterone and renin levels,25 and a turning off of the serum RAS while the tissue RAS remained active during healing.26 Protection from potentially undesirable effects of systemic and local tissue ACE, circulating and local angiotensin II and noradrenaline, and circulating aldosterone and other neurohormones26 27 might all have played a role in cardioprotection and prevention of hypertrophy with enalapril. However, the fact that ACE is activated in acute myocardial infarction26 suggests that local ACE inhibition by enalapril blocked intramyocardial conversion of angiotensin I to angiotensin II, resulting in decreased local angiotensin II and inhibition of myocyte and fibroblast growth factors. This mechanism could explain prevention of hypertrophy of noninfarcted myocardium in our study and is supported by the finding of regression of hypertrophy in the pressure-overload rat model with a dose of the ACE inhibitor ramipril that did not lower blood pressure.28
Paradoxical Effects on Infarct and Noninfarct Collagen Matrix
Several lines of evidence suggest that the extracellular framework
plays an important role in postinfarct remodeling and that
antiremodeling therapy might modify the framework.2 Both
regional and global ventricular dilation can result from and cause
damage to the extracellular collagen matrix.2 Thus,
ischemia damages the collagen matrix and contributes to regional
dilation.29 30 Pacing-induced heart failure is
associated
with upregulation of collagenases and metalloproteinases that degrade
collagen and probably mediate nonischemic ventricular
enlargement.31 Elevated regional wall stress and shearing
forces associated with regional diastolic
bulging5 7 8 15
could produce mechanical damage of extracellular matrix and promote
progressive remodeling during postinfarct healing. Ventricular
unloading and decreased wall stresses from ACE inhibition could
therefore protect against matrix disruption. However, because ACE
inhibition blocks local angiotensin II, thereby decreasing the activity
of fibroblast growth factor and transforming growth factor–ß
(TGF-ß) (the latter being a potent modulator of the extracellular
matrix and a stimulator of collagen synthesis32 ), the
potential exists for greater remodeling in infarct and noninfarct
regions that might offset some of the benefits of ACE inhibition,
especially with large infarcts.
In noninfarction rat models of hypertension, increased myocardial collagen associated with increased angiotensin II and aldosterone is thought to be harmful,27 and prolonged ACE inhibition causing unopposed collagen degradation, decreased collagen content, and regression of fibrous tissue is considered beneficial.33 34 In contrast, in the rat model of infarction, in which infarcts are large, dilation is pronounced, and noninfarct collagen content increases,35 36 captopril given early35 during healing postinfarction but not later36 inhibits DNA synthesis, fibroblast proliferation, and collagen deposition in the noninfarct myocardium,35 a series of changes associated with hemodynamic deterioration.37 Another ACE inhibitor, perindopril, given 1 week after infarction in the rat also decreased noninfarct collagen volume and partially reversed the isomyosin profile.25 In a recent study, the angiotensin II receptor antagonist losortan, given during postinfarction healing, completely inhibited noninfarct collagen deposition in the rat.38 Although these studies did not measure infarct collagen, it is reasonable to speculate that ACE inhibition might also have inhibited collagen deposition in the infarct zone in the rat model. Because angiotensin II increases expression of the TGF-ß1 gene,32 and TGF-ß1 is increased in rat infarction,39 inhibition of angiotensin II and TGF-ß1 might be especially important mediators of this effect.
In the dog infarction model, in which infarcts are smaller, ventricular dilation is less marked, and noninfarct collagen does not increase compared with the rat, early and prolonged ACE inhibition with captopril was found to limit remodeling but did not significantly decrease noninfarct or infarct collagen.7 8 In the present study, enalapril somewhat paradoxically decreased infarct collagen but not noninfarct collagen and both regional and global dilation. No differences in collagen content or histology were found in noninfarcted myocardium of the control and enalapril groups, but collagen content in the infarct zone of the enalapril group was lower than in the control group, suggesting enalapril-induced inhibition of fibroblast activity and collagen deposition in the infarct zone during the early phase of healing. Less infarct collagen might, in turn, explain the altered topography with flattening of the infarct scar (ie, decrease in transmural scar thickness and increase in angular extent compared with the control group) while the total area of the scar was retained (ie, similar scar area in the two groups). Thus, less infarct collagen during healing might allow more remodeling of the infarct zone to occur under the sustained action of intracavitary and intramural deforming forces.2 Increased collagenase activity and production of new collagen secondary to ACE inhibition might have contributed to reshaping of the collagen framework. It is possible that the lesser infarct collagen content in the enalapril group might have weakened the scar, although the mechanical strength was not measured. One possible explanation for the paradoxical decrease in infarct collagen but not noninfarct collagen is that the dose of enalapril was sufficient to inhibit collagen deposition that was already occurring in the healing infarct zone of the dog model. The overall findings suggest that ACE inhibitors might not influence remodeling parameters uniformly. The balance between the protective effects of ACE inhibition on mechanical disruption of the matrix and the potentially harmful effects of ACE inhibition on infarct collagen and matrix in noninfarct zones would be expected to influence eventual outcome.
Other Studies of ACE Inhibition and Remodeling
Most studies
pertinent to the modification of remodeling after
infarction by ACE inhibition have focused on beneficial effects on
hemodynamics, ventricular enlargement, and survival after large
infarcts in the rat. Captopril has been studied more
extensively.3 6 9 10 25 40 41
Although these studies
provide insight into underlying mechanisms, only two addressed effects
on collagen or matrix.7 8 Intravenous captopril
during
acute infarction in the anesthetized dog increased collateral flow and
decreased mean arterial pressure, left atrial pressure, and infarct
size.40 However, it did not decrease infarct size in the
conscious dog, probably because of hypotension.41 A
similar phenomenon was demonstrated with intravenous nitroglycerin,
which decreased infarct size18 and
remodeling19 when given in low dose during infarction in
the conscious dog but produced no decrease or even a paradoxical
increase in infarct size at higher hypotensive doses.18 A
study comparing the effects of captopril and hydralazine in rats with
large infarctions underscored the importance of venodilation and
preload reduction rather than afterload reduction in the prevention of
ventricular dilation.42 Prolonged administration of
captopril between 2 days and 6 weeks after nontransmural7
and transmural8 anterior infarction in the conscious dog
limited ventricular dilation and improved function but did not reduce
infarct or noninfarct collagen. Human studies with captopril have
demonstrated limitation of ventricular dilation, preservation of
function, and improvement of survival.9 10
Enalapril has been studied less extensively than
captopril.11 13 43 44 45 46
In one study with prolonged
enalapril and milrinone after healed infarction in the rat, Sweet et
al43 found that enalapril and milrinone both decreased
ventricular hypertrophy and prolonged survival, but there was no
evidence of synergism between the two agents for the survival end
point. Also in the rat model, prolonged therapy with either enalapril
or propionyl-L-carnitine decreased ventricular
dilation.44 However, in the CONSENSUS II trial, which
tested the hypothesis that enalapril begun in humans within 24
hours of the onset of acute infarction and continued for 6 months might
improve survival, no benefit was seen, and early hypotension might have
contributed to the excess in early mortality.12 In 11
patients with congestive heart failure, 3 months of enalapril therapy
resulted in regression of left ventricular dilation without improvement
in contractility.45 Recently, Sigurdsson et
al46 studied neurohormones in a subset of 98 patients from
the CONSENSUS II trial and remodeling in 28 of the patients with
echocardiograms (15 placebo, 13 enalapril) and found a correlation
between circulating catelcholamine levels at days 5 to 7 after
infarction and subsequent ventricular enlargement, supporting the
hypothesis that sustained neurohumoral activation after acute
infarction is harmful and contributes to ventricular remodeling and
dysfunction. In the SOLVD prevention trial, in which about 80% of
patients had infarction and all had ejection fractions 35%,
enalapril therapy did not significantly improve
survival.11 In the SOLVD treatment trial, enalapril
decreased mortality47 and progression of ventricular
dilation was delayed,13 but in some patients systolic and
diastolic wall stress were not normalized.13 In the
recently published AIRE trial, ramipril decreased mortality in patients
with heart failure after infarction.48 There was no report
of excess mortality from ventricular rupture in the CONSENSUS II,
SOLVD, or AIRE trials, but infarct topography was not studied.
Whether the absence of a sulfhydryl moiety in enalapril and its presence in captopril might explain the minor differences between the results of the present study and our previous studies7 8 with captopril is uncertain. A comparative study of the effects of the ACE inhibitors spirapril (with a sulfhydryl group) and zofenopril (without a sulfhydryl group) on remodeling over 6 weeks after infarction in the rat model revealed similar attenuation of ventricular dilation and hypertrophy and no demonstrable advantage attributable to the sulfhydryl group.49 However, it has been proposed that the sulfhydryl moiety acts as an oxygen free radical scavenger, and ACE inhibitors containing this group have been suggested to reduce reperfusion damage.50 No interaction between the sulfhydryl group and collagen is known to date.
Implications
The overall results of this study indicate that
ACE inhibition
with enalapril, in a dose that does not lower blood pressure, produces
prolonged reduction in left ventricular preload that is associated with
a beneficial limitation of infarct expansion and thinning and of
ventricular dilation, aneurysm formation, and hypertrophy and with an
improvement in ventricular systolic function. However, enalapril
therapy was also associated with a decrease in infarct collagen content
and alteration in scar topography. This effect on infarct collagen
content might be more marked when larger doses of enalapril are used
and when the infarctions are larger. Such an effect might partially
explain the result of early enalapril therapy in the CONSENSUS II
clinical trial.12 Similarly, the inhibition of ventricular
hypertrophy with long-term enalapril therapy might be a disadvantage
with large infarctions, especially if it were to exceed the decrease in
ventricular dilation, resulting in a mismatch between ventricular
volume and wall thickness. Such an effect might partially explain the
lack of improvement in wall stress in some patients in the SOLVD
trial.13
Conclusions
Enalapril therapy in a dose that does not lower
blood pressure,
beginning 1 day after anterior infarction and maintained throughout the
healing phase and perhaps even after, might be very effective in
preserving left ventricular geometry and function. However, the effects
on reactive hypertrophy and infarct collagen should be borne in mind
when treating large infarctions and severe left ventricular
dysfunction.
|
Acknowledgments |
|---|
This study was supported in part by grants from the Medical Research Council of Canada and the Canadian Heart and Stroke Foundation, Ottawa, Ontario. This work was performed during the tenure of Dr Jugdutt as a Scientist of the Alberta Heritage Foundation for Medical Research. We are grateful to Merck-Frosst Canada, Inc, for the free supply of enalapril for pilot studies. We also thank Jack Demare and Leanne Pearson for technical assistance, Vijayan Menon, BSc, for computer operations and statistics, and Catherine Graham for typing.
|
Footnotes |
|---|
Reprint requests to Dr B.I. Jugdutt, 2C2.43 Walter Mackenzie Health Sciences Centre, Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2R7.
Received July 20, 1994; accepted September 5, 1994.
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References |
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