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2852
Effects of Long-term Monotherapy With Enalapril,
Metoprolol, and Digoxin on the Progression
of Left Ventricular Dysfunction and
Dilation in Dogs With
Reduced Ejection Fraction
Hani N. Sabbah, PhD; Hisashi Shimoyama, MD; Tatsuji Kono, MD; Ramesh C. Gupta, PhD;
Victor G. Sharov, MD, PhD; Gloria Scicli, PhD; T. Barry Levine, MD; Sidney Goldstein, MD
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Background Recent clinical trials have suggested that therwith angiotensin-converting enzyme inhibitors in asymptomatic patients with reduced left ventricular (LV) function
can significantly reduce the incidence of congestive heart
failure compared with patients receiving placebo. In the
present study, we examined the effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression
of LV systolic dysfunction and LV chamber enlargement in
dogs with reduced LV ejection fraction (EF).
Methods and Results LV dysfunction was produced in 28
dogs by multiple sequential intracoronary microembolizations.
Embolizations were discontinued when LVEF was 30% to
40%. Three weeks after the last embolization, dogs were
randomized to 3 months of oral therapy with enalapril (10 mg
twice daily, n=7), metoprolol (25 mg twice daily, n=7), digoxin
(0.25 mg once daily, n=7), or no treatment (control, n=7). As
expected, in untreated dogs, LVEF decreased (36 + 1% versus
26+1%, P<.001) and LV end-systolic volume (ESV) and
end-diastolic volume (EDV) increased during the 3-month
follow-up period (39±4 versus 57±6 mL, P<.001, and 61±6
versus 78±8 mL, P<.002, respectively). In dogs treated with
enalapril or metoprolol, LVEF remained unchanged or increased after therapy compared with before therapy (35±1%
versus 38±3% and 35±1% versus 40±3%, respectively,
P<.05), whereas ESV and EDV remained essentially unchanged. In dogs treated with digoxin, EF remained unchanged but ESV and EDV increased significantly.
Conclsions In dogs with reduced LVEF, long-term therapy
with enalapril or metoprolol prevents the progression of LV
systolic dysfunction and LV chamber dilation. Therapy with
digoxin maintains LV systolic function but does not prevent
progressive LV enlargement. (Circulation. 1994;89:2852-2859.)
Key Words * (3-blockers * angiotensin-converting enzyme
inhibitors * digitalis
eft ventricular (LV) dysfunction, once established as a result of a primary event such as
compensatory
are elicited to maintain homeostasis beresponsible in part for the progressive deterioration of LV function.10"'1
Recent clinical studies have focused on the introduction of early therapy in asymptomatic patients with
reduced LV performance in an attempt to prevent this
"autoinduction" of LV dysfunction and therefore avoid
or, at the very least, retard the progression toward overt
heart failure.'2 In the prevention arm of the SOLVD
(Studies of Left Ventricular Dysfunction) trial, longterm treatment of asymptomatic patients with reduced
LV ejection fraction (.35%) with the angiotensinconverting enzyme (ACE) inhibitor enalapril significantly reduced the incidence of congestive heart failure
and the rate of associated hospitalizations compared
with placebo-treated patients.12 In asymptomatic patients with reduced LV ejection fraction (c40%) after
myocardial infarction who were treated long-term with
the ACE inhibitor captopril, the SAVE (Survival and
Ventricular Enlargement) trial showed improvement in
survival and reduced incidence of congestive heart
Received October 28, 1993; revision accepted March 17, 1994.
From the Division of Cardiovascular Medicine, Henry Ford
Heart and Vascular Institute, Detroit, Mich.
Reprint requests to Hani N. Sabbah, PhD, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202.
results of these clinical trials clearly indicate that early
treatment with ACE inhibitors in patients with reduced
LV ejection fraction has beneficial effects on long-term
outcome. It should be recognized that in all of these
studies, because of the nature of clinical trials, ACE
apy
acute
myocardial infarction,
can worsen over a
period of months or years despite the absence of
concurrent clinical events.1-3 This process of progressive
LV dysfunction often culminates in the syndrome of
congestive heart failure. The exact mechanism or mechanisms that underlie this progressive deterioration of
LV function are not known. When significant loss of
viable myocardium occurs as a result of myocardial
infarction, compensatory mechanisms including ventricular dilation4,5 and hypertrophy67 of the residual myocardium are engaged to maintain pump function. When
these compensatory systems fail to maintain cardiac
output, peripheral vasoconstriction develops with the
objective of maintaining perfusion pressure to vital
organs. Enhanced activity of the sympathetic nervous
system and the renin-angiotensin system are two primary contributors to the increased systemic vascular
resistance that characterizes the heart failure state.8,9 It
is often postulated that the
very same
systems that
come
failure compared with placebo-treated patients.13 The
Sabbah et al Progression of LV Function
inhibitors were examined in the presence of other
concommitant medications that frequently included
P-blockers, calcium channel blockers, vasodilators, digitalis, and diuretics.12,3 The present study was designed
to determine the effects of monotherapy with the ACE
inhibitor enalapril, the p-blocker metoprolol, and the
digitalis preparation digoxin on the progression of LV
systolic dysfunction and dilation in dogs with reduced
LV ejection fraction.
Methods
Preparation of the Animal Model
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Twenty-eight healthy mongrel dogs weighing between 18
and 31 kg were used in the study. Chronic LV dysfunction was
produced by multiple sequential intracoronary embolizations
with polystyrene latex microspheres (77 to 102 gm in diameter), as previously described.'4 Coronary microembolizations
were performed during sequential cardiac catheterizations
under general anesthesia and sterile conditions. The anesthesia regimen used in the present study consisted of a combination of intravenous injections of oxymorphone hydrochloride
(0.22 mg/kg), diazepam (0.17 mg/kg), and sodium pentobarbital (150 to 250 mg to effect). This anesthesia regimen was
effective in preventing the tachycardia, hypertension, and
myocardial depression often seen in dogs anesthetized with
pentobarbital alone. To determine the effects of anesthesia on
LV function, two-dimensional echocardiograms were obtained
in four untreated dogs with heart failure (not included in the
present study) before anesthesia (conscious state) and after
induction of anesthesia. A midpapillary LV short-axis crosssectional view was used to calculate the percent fractional area
of shortening (FAS) defined as the difference between the
end-diastolic area and the end-systolic area divided by the
end-diastolic area times 100. There was no difference between
FAS measured before anesthesia (34±2%) compared with
that measured after induction of anesthesia (35±2%). In all
dogs, coronary microembolizations were discontinued when
LV ejection fraction, determined angiographically, was between 30% and 40%. To achieve this target ejection fraction,
dogs underwent an average of 5.3 microembolization procedures performed over an average period of 8.8 weeks. Microembolization procedures were performed 1 to 3 weeks apart.
Left ventriculograms were performed before each embolization procedure to assess ejection fraction.
Study Protocol
Three weeks after the last embolization procedure, all dogs
underwent a prerandomization left and right heart catheterization. The 3-week period between the last embolization and
the prerandomization cardiac catheterization procedure was
allowed to ensure that all infarctions produced by the last
embolization were completed. One day after cardiac catheterization, dogs were randomized to 3 months of oral monotherapy with enalapril (10 mg twice daily, n=7), metoprolol (25 mg
twice daily, n=7), digoxin (0.25 mg once daily, n=7), or no
treatment at all (control arm, n=7). None of the dogs in any of
the four study groups received any medication aside from the
specified study drugs during the 3-month follow-up period.
Hemodynamic, angiographic, and neurohormonal measurements were made at baseline, before any embolizations, and
were repeated 1 day before randomization and initiation of
therapy and 3 months after initiating therapy. All hemodynamic and angiographic measurements were made during
cardiac catheterizations. Dogs were killed after the final
hemodynamic study (3 months after initiating therapy). The
study was approved by the Henry Ford Hospital Care of
Experimental Animals Committee and conformed to the guiding principles of the American Physiological Society.
2853
Study End Points
The primary study end point was progression of LV
systolic dysfunction based on LV ejection fraction determined
angiographically. A secondary end point was progression
of LV chamber dilation based on (1) a progressive increase of
LV end-systolic volume and (2) a progressive increase of LV
end-diastolic volume.
Hemodynamic Measurements
Aortic and LV pressures were measured with cathetertipped micromanometers (Millar Instruments). Mean pulmonary artery wedge pressure and mean right atrial pressure
were measured using a Swan-Ganz catheter in conjunction
with a P23 XL pressure transducer (Spectramed). Cardiac
output was measured in triplicate using the thermodilution
method. LV stroke volume was calculated as the ratio of
cardiac output to heart rate. Systemic vascular resistance was
calculated as the difference between mean aortic pressure and
mean right atrial pressure times 80 divided by cardiac output.
Left ventricular end-diastolic wall stress was calculated according to the equation'5
Wall stress=Pb/h(1-h/2b)(1-hb/2a2)
where P is LV end-diastolic pressure, a is LV major semiaxis,
b is LV minor semiaxis, and h is LV wall thickness. LV wall
thickness and the major and minor semiaxes were measured
from echocardiograms obtained during each study cardiac
catheterization, as previously described.16
Ventriculographic Measurements
Single-plane left ventriculograms were obtained during each
cardiac catheterization after completion of the hemodynamic
measurements with the dog placed on its right side. Ventriculograms (approximately 600 right anterior oblique projection)
were recorded on 35 mm cinefilm at 30 frames per second
during the injection of 20 mL of contrast material (Hypaque
meglumine 60%, Winthrop Pharmaceuticals). Correction for
image magnification was made with a radiopaque calibrated
grid placed at the level of the left ventricle. LV end-systolic
and end-diastolic volumes were calculated from ventricular
silhouettes using the area-length method.17 The LV ejection
fraction was calculated as the ratio of the difference of
end-diastolic volume and end-systolic volume to end-diastolic
volume times 100. Extrasystolic and postextrasystolic beats
were excluded from all analyses involving ventriculograms.
Neurohormonal Assessments
Venous blood samples were obtained from conscious dogs 1
day before cardiac catheterization for evaluation of the plasma
concentration of several neurohormones. To minimize any
possible variations, blood samples were obtained between 9:00
and 10:00 AM with the dogs in a fasting state. Plasma norepinephrine concentration was measured using aluminum oxide
absorption by high-performance liquid chromatography. In
our laboratory, this technique has a day-to-day coefficient of
variation of 6.8%. Plasma renin activity was evaluated by
radioimmunoassay for generation of angiotensin-I based on
modification of the method of Haber et al.18 Immunoreactive
atrial natriuretic factor in plasma was determined by radioimmunoassay as described by Shenker et al.19 Venous blood
samples were obtained once a week from dogs treated with
digoxin and used for determination of plasma digoxin level.
Data Analysis
Intragroup Comparisons
The primary objective of the study was to determine the
effects of long-term monotherapy with enalapril, metoprolol,
or digoxin on the progression of LV systolic dysfunction and
dilation. Accordingly, comparisons of each hemodynamic,
2854
Circulation Vol 89, No 6 June 1994
TABLE 1. Baseline Hemodynamic and Angiographic Measurements During Cardiac Catheterization
Control
Enalapril
Metoprolol
Digoxin
n=7
82±6
102±7
6±1
53±4
n=7
78±6
106±7
6±1
49±2
n=7
n=7
77±5
80±4
Mean AoP, mm Hg
107±4
113±10
LVEDP, mmHg
5±1
6±1
48±4
SV, mL
46±3
7±1
7±1
7±1
Mean PAWP, mmHg
6±1
1810±110
2260±270
2380±190
SVR, dyne. sec * cm-5
2380±130
LVEF, %
59±3
57±3
53±1
56±3
24±2
LVESV, mL
28±3
30±2
30±3
60±7
LVEDV, mL
64±2
67±5
67±4
21±4
Wall stress, g/cm2
23±2
20±4
24±4
HR indicates heart rate; AoP, aortic pressure; LVEDP, left ventricular end-diastolic pressure; SV, stroke volume;
PAWP, pulmonary artery wedge pressure; SVR, systemic vascular resistance; LV, left ventricular; EF, ejection
fraction; ESV, end-systolic volume; and EDV, end-diastolic volume.
HR, beats per minute
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angiographic, and neurohormonal variable within each of the
four study groups were examined between measurements
obtained just before the initiation of therapy and measurements made after completion of 3 months of therapy. For
these comparisons, a Student's paired t test was used, and a
probability value of c.05 was considered significant.
Intergroup Comparisons
To ensure that the hemodynamic, angiographic, and neurohormonal parameters at baseline and before initiation of
therapy were similar between the untreated group and each of
the actively treated groups, comparisons were made using a t
statistic for two means. For this test, a probability value of
.05 was considered significant.
Significance of treatment effect was examined by comparing
the mean posttreatment hemodynamic, angiographic, and neurohumoral measures between the control (untreated) group
and each of the three treatment groups after adjusting for
pretreatment values. For these comparisons, an ANCOVA
model was used. Because for each measure three comparisons
were of interest (control versus enalapril, control versus metoprolol, and control versus digoxin), a Bonferroni-adjusted a
level of 0.017 was considered significant. Probability values
between .05 and .017 were considered marginally significant.
All data are reported as mean±SEM.
Results
All dogs entered into the study had hemodynamic,
angiographic, and neurohormonal findings that were
within the normal range for dogs in our laboratory.
These data, obtained at baseline, before any embolizations, are shown in Tables 1 and 2 for all four study
groups. There were no significant differences in any of
the baseline parameters between dogs that were subsequently randomized to no treatment and dogs random-
ized to active treatment with enalapril, metoprolol, or
digoxin. Furthermore, there were no significant differences in any of the hemodynamic, angiographic, and
neurohormonal variables measured just before randomization, and the initiation of therapy between dogs
randomized to no treatment and dogs randomized to
treatment with enalapril, metoprolol, or digoxin. These
data are shown in Tables 3 and 4 and Figs 1 through 3.
Effects of No Treatment on the Progression of LV
Dysfunction and Dilation
In dogs randomized to no treatment (control arm), LV
ejection fraction decreased significantly during the
3-month follow-up period (36±1% versus 26±1%,
P<.001) (Fig 1). The decline in LV ejection fraction was
accompanied by a progressive increase in LV end-systolic
volume (39±4 versus 57±6 mL, P<.001) (Fig 2) and LV
end-diastolic volume (61±6 versus 78±8 mL, P<.002)
(Fig 3). Lack of therapy in this group of dogs during the
3-month follow-up period was associated with a significant
reduction of LV stroke volume and significant increases of
heart rate, mean aortic pressure, systemic vascular resistance, and plasma norepinephrine concentration (Tables
3 and 4). LV end-diastolic wall stress, plasma renin
activity, and plasma atrial natriuretic factor were not
significantly different at the end of the 3-month follow-up
period compared with the start of the follow-up period
(Tables 3 and 4).
Effects of Monotherapy With Enalapril
In dogs treated with enalapril, LV ejection fraction
was 35±1% before the initiation of therapy and remained essentially unchanged at 38±3% after comple-
TABLE 2. Baseline Plasma Neurohumoral Levels Measured in Conscious Dogs 1 Day Before
Cardiac Catheterization
Control
Enalapril
Metoprolol
Digoxin
n=7
n=7
n=7
PNE, pg/mL
325±28
256+38
326±38
350±41
PRA, ng/mL per hr
1.4±0.5
1.4±0.4
1.0±0.3
0.8±0.2
ANF, pg/mL
18±3
25±7
27±5
22±1
PNE indicates plasma norepinephrine; PRA, plasma renin activity; and ANF, plasma atrial natriuretic factor.
n=7
Sabbah et al Progression of LV Function
2855
TABLE 3. Hemodynamic Measurements Obtained Before Initiation of Therapy and 3 Months After Initiation of Therapy
Control (No Therapy)
Pre
HR, beats per minute
MeanAoP, mmHg
LVEDP, mm Hg
SV, mL
Mean PAWP, mm Hg
SVR, dyne. sec* cm-5
Wall stress, g/cm2
Enalapril
P
<.001
<.05
<.56
<.003
<.93
<.05
<.72
Post
97+8
79±7
95+5
109±5
17+3
36±3
10±1
2620±250
74±12
20+5
29±2
11±2
3000±150
80±21
Metoprolol
Pre
87+5
94+7
21±4
35±3
13±3
2390±150
79±16
Post
81±4
90±6
16±4
39±3
13±3
2250±210
71±19
Digoxin
P
<.28
<.56
<.23
<.03
<.66
<.51
<.55
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P
Pre
Post
P
Pre
Post
HR, beats per minute
95±8
83±6
<.28
84±4
99±19
<.40
Mean AoP, mm Hg
107±4
98±4
<.09
102±6
103±9
<.91
LVEDP, mm Hg
18±3
10±2
<.02
13±1
12±1
<.45
SV, mL
35±3
40±3
<.12
37±6
34±4
<.54
Mean PAWP, mm Hg
11±2
9±1
<.42
9±1
8±1
<.49
SVR, dyne. sec. cm-5
2650±300
2340±240
<.37
2810+360
2540+230
<.50
Wall stress, g/cm2
78±13
43±8
<.01
52±7
49±8
<.82
HR indicates heart rate; AoP, aortic pressure; LVEDP, left ventricular end-diastolic pressure; SV, stroke volume; PAWP, pulmonary
artery wedge pressure; and SVR, systemic vascular resistance.
tion of 3 months of therapy (Fig 1). Similarly, there was
no progressive increase of LV end-systolic volume
(40±4 versus 40±3 mL) or LV end-diastolic volume
(61±6 versus 65±5 mL) in this group of dogs between
measurements obtained
at
start of therapy and
thele
those obtained at the end of 3 months of therapy (Figs
2 and 3). The absence of progressive deterioration of
LV function in dogs treated with enalapril was associated with a moderate but significant increase of stroke
volume, whereas heart rate, mean aortic pressure, systemic vascular resistance, LV end-diastolic wall stress,
and plasma norepinephrine concentration were not
significantly altered (Tables 3 and 4). As expected,
plasma renin activity increased significantly with enalapril therapy (Table 4). Atrial natriuretic factor tended
to decrease with enalapril therapy, but the difference
was not statistically significant (Table 4).
Effects of Monotherapy With Metoprolol
In dogs treated with metoprolol, LV ejection fraction
increased significantly from 35±1% just before initiation of therapy to 40±3% after completion of 3 months
of therapy (P<.04) (Fig 1). There were no significant
increases in
LV end-systolic volume (41+3 versus
ices
in either
er
LV end-systolic volume (64±3 versus
41±3 mL) or LV end-diastooli volume (64±3 versus
69±4 mL) during metoprolol therapy (Figs 3 and 4).
Therapy with metoprolol was associated with a significant reduction of LV end-diastolic pressure and LV
end-diastolic wall stress, whereas heart rate, mean
aortic pressure, systemic vascular resistance, and plasma
norepinephrine concentration remained unaltered (Tables 3 and 4). Plasma renin activity increased modestly
but significantly. Stroke volume tended to increase and
plasma atrial natriuretic factor tended to decrease with
TABLE 4. Plasma Neurohumoral Levels Measured Before Initiation of Therapy and 3 Months After Initiation
of Therapy
Control (No Therapy)
PNE, pg/mL
PRA, ng/mL per hr
ANF, pg/mL
Pre
372±40
1.2±0.3
60+10
Pre
Post
569±44
1.5±0.3
62±11
Metoprolol
Post
413±38
422±69
PNE, pg/mL
0.9±0.3
2.1±0.3
PRA, ng/mL per hr
49±10
40±4
ANF, pg/mL
PNE indicates plasma norepinephrine; PRA, plasma renin activity;
Enalapril
P
<.006
<.60
<.80
Pre
366±65
Post
464±88
1.4±.4
70±15
4.2±0.5
54+17
P
<.44
<.008
<.30
Digoxin
P
<.81
<.05
<.70
and ANF, plasma
Pre
Post
424±80
335±47
1.0±0.3
1.3±0.7
55±11
55±15
atrial natriuretic factor.
P
<.26
<.68
<.96
2856
Circulation Vol 89, No 6 June 1994
1
_
t--
Pre-Theropy
M Post-Therapy
p(O.O4
~~~~~~p<O.32
_
E
10uu-
p(O.002
MPrs-Th.rmpy
Post-Therapy p(o.001
E 80
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FIG 1. Bar graph depicting values (mean+±SEM) of left ventricular (LV/) ejection fraction before initiation of therapy and after
completion of therapy. Values are shown for the control untreated dogs (CON), dogs treated with enalapril (ENA), dogs
treated with metoprolol (MET), and dogs treated with digoxin
(DIG). Probabilities refer to comparisons between pretherapy
and posttherapy values for each study group.
FIG 3. Bar graph depicting values (mean2SEM) of left ventricular (LV) end-diastolic volume before initiation of therapy and
after completion of therapy. Values are shown for the control
untreated dogs (CON), dogs treated with enalapril (ENA), dogs
treated with metoprolol (MET), and dogs treated with digoxin
(DIG). Probabilities refer to comparisons between pretherapy
and posttherapy values for each study group.
metoprolol therapy, but these changes were not statistically significant (Table 4).
Effects of Monotherapy With Digoxin
The average plasma digoxin level over the 3-month
therapy period was 0.96±0.11 ng/mL. In dogs treated
with digoxin, LV ejection fraction was 35+±1% before
the initiation of therapy and remained essentially unchanged at 34±1% after completion of 3 months of
therapy (Fig 1). In contrast to therapy with enalapril
and metoprolol, monotherapy with digoxin did not
0
prevent
progressive LV dilation. In these dogs, LV
end-systolic volume measured after completion of therapy (52±4 mL) was significantly greater than before
therapy (43+±4 mL) (P< .008) (Fig 2). Similarly, LV
end-diastolic volume
therapy comCON wasENAgreaterMETafter DIG
pared with before therapy (79±5 versus
67±6 mL)
(P< .001)(Fig 3). Monotherapy with digoxin had no
significant effects on heart rate, mean aortic pressure,
LV end-diastolic pressure, stroke volume, systemic vascular resistance, LV end-diastolic wall stress, plasma
norepinephrine concentration, plasma renin activity, or
plasma atrial natriuretic factor (Tables 3 and 4).
Comparisons of Posttreatment Measures
(Treatment EffSect)
In the posttreatment analysis, each of the three active
treatment groups (enalapril, metoprolol, and digoxin)
were compared with the control group. The probability
values are shown in Tables 5 and 6. LV ejection fraction
was significantly higher in all three treatment groups in
comparison to controls. LV end-diastolic volume was
lower than control in the enalapril-treated group and
the metoprolol-treated group but not in the digoxintreated group. LV end-systolic volume was significantly
lower than control in all three treated groups. Although
significantly lower than control, end-systolic volume in
the digoxin-treated group was substantially higher than
that observed in the enalapril- and metoprolol-treated
groups (Fig 2). Heart rate and stroke volume were
significantly lower than control only in the enalapril and
metoprolol groups (Table 5). Systemic vascular resistance was lower than control (marginally significant)
only in the enalapril- and metoprolol-treated groups.
LV end-diastolic pressure and wall stress were lower
than control (marginally significant) only in the metoprolol-treated group (Table 5). Plasma norepinephrine
concentration was lower than control (marginally significant) only in the digoxin-treated group (Table 6). Atrial
natriuretic factor was not significantly different than
controls in any of the three treated groups (Table 6).
Discussion
Consistent with our previous studies,14 20 the results of
the present study indicate that in the absence of any
therapeutic interventions, progressive deterioration of
LV systolic function and progressive LV chamber dilation occur in dogs with reduced LV ejection fraction
resulting from loss of viable LV myocardium. In contrast, dogs with reduced LV ejection fraction randomized to early monotherapy with enalapril or metoprolol
did not manifest progressive LV systolic dysfunction or
progressive LV chamber enlargement. The results also
indicate that early therapy with digoxin, although effective in maintaining LV ejection fraction, does not appear to have a beneficial impact on progressive LV
enlargement.
The observation of this study that monotherapy with
enalapril prevents the progressive deterioration of LV
systolic function and LV chamber enlargement is consistent with the results and supports the conclusions of
several recent clinical trials.'2"l3 In the prevention arm
of the SOLVD trial, early treatment with enalapril in
asymptomatic patients with reduced LV ejection frac-
E-p30.-s_
Pre-Therpy
T
1Z1 ~~~~Post-Therapy
w.a
FIG 2. Bar graph depicting values (mean+SEM) of left ventricular (LV) end-systolic volume before initiation of therapy and
after completion of therapy. Values are shown for the control
untreated dogs (CON), dogs treated with enalapril (ENA), dogs
treated with metoprolol (MET), and dogs treated with digoxin
(DIG). Probabilities refer to comparisons between pretherapy
and posttherapy values for each study group.
Sabbah et al Progression of LV Function
2857
TABLE 5. Treatment Effect Probability Values for Comparisons Between the Control Group and
Each of the Three Active Treatment Groups
Metoprolol
Enalapril
Dlgoxin
vs
vs
vs
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Control,
Control,
Control,
p
p
p
<.002
HR, beats per minute
<.006
<.87
<.25
<.045
<.030
Mean AoP, mm Hg
<.23
<.019
<.18
LVEDP, mm Hg
<.14
<.001
<.002
SV, mL
<.48
<.48
<.98
Mean PAWP, mm Hg
<.021
<.025
<.08
SVR, dyne.sec cm5
<.012
<.001
<.001
LVEF, %
<.014
<.001
<.001
LVESV, mL
<.35
<.024
<.008
LVEDV, mL
<.47
<.44
<.031
Wall stress, g/cm2
HR indicates heart rate; AoP, aortic pressure; LVEDP, left ventricular end-diastolic pressure; SV, stroke volume;
PAWP, pulmonary artery wedge pressure; SVR, systemic vascular resistance; LV, left ventricular; EF, ejection
fraction; ESV, end-systolic volume; and EDV, end-diastolic volume.
tion was shown to reduce the incidence of congestive
heart failure and associated hospitalizations as well as a
trend toward fewer deaths due to cardiovascular causes
compared with patients given placebo.12 In a subset of
patients with mild to moderate heart failure and reduced LV ejection fraction (c35%) enrolled in the
treatment arm of the SOLVD trial, long-term treatment
with enalapril also was shown to prevent progressive LV
enlargement compared with patients randomized to
placebo.3 In this subset study, patients randomized to
placebo manifested a significant increase in LV end-diastolic and end-systolic volumes, whereas patients randomized to enalapril manifested modest but significant
improvements in LV end-systolic and end-diastolic volumes and LV ejection fraction after 1 year of therapy.3
In patients with a first anterior myocardial infarction
and reduced LV ejection fraction (<45%), early therapy with captopril also was shown to attenuate the
process of progressive LV dilation.21
Unlike studies with ACE inhibitors, there are no
clinical trials to date that have examined the effects of
early therapy with p-blockers on the progression of LV
dysfunction and enlargement in asymptomatic patients
with reduced LV ejection fraction. The results of the
present study in dogs suggest that early therapy with
metoprolol is as effective as enalapril in preventing the
progressive deterioration of LV function and the progression of LV dilation. Several clinical studies have
demonstrated beneficial effects of long-term ,B-blockade
in symptomatic patients with idiopathic dilated cardiomyopathy22-25 or ischemic cardiomyopathy.26,27 In patients with symptomatic heart failure due to dilated
cardiomyopathy and an average LV ejection fraction of
25%, a 3-month treatment with bucindolol resulted in
improvement of LV ejection fraction and New York
Heart Association (NYHA) functional class compared
with patients randomized to placebo.24 In patients with
severe heart failure due to ischemic cardiomyopathy
with an average LV ejection fraction of 23%, long-term
therapy with metoprolol was associated with marked
improvement of LV ejection fraction.26 As with all of
these clinical studies, early long-term therapy with
metoprolol in the present study was also associated with
a significant increase of LV ejection fraction.
As with ,B-blockers, there are no major clinical trials
to date that have examined the effects of early digoxin
therapy on the progression of LV dysfunction and
dilation in asymptomatic patients with reduced LV
ejection fraction. The results of the present study suggest that early long-term monotherapy with digoxin in
dogs with reduced LV ejection fraction prevents the
progressive decline in LV ejection fraction but does not
impede the process of progressive LV dilation. These
observations are consistent with observations made in a
recent study of patients with anterior myocardial infarction.28 In this study, 40 patients were randomized to
TABLE 6. Treatment Effect Probability Values for Comparison of Neurohormones Between the
Control Group and Each of the Three Active Treatment Groups
Digoxin
Metoprolol
Enalapril
vs
vs
vs
Control,
Control,
Control,
p
<.020
<.27
PNE, pg/mL
<.79
<.001
PRA, ng/mL per hr
<.80
<.25
ANF, pg/mL
PNE indicates plasma norepinephrine; PRA, plasma renin activity; and ANF, plasma atrial natriuretic factor.
p
p
<.13
<.043
<.59
2858
Circulation Vol 89, No 6 June 1994
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1-year treatment with captopril or digoxin 7 to 10 days
after the onset of symptoms.28 In patients treated with
digoxin, the LV end-systolic and end-diastolic volume
indexes increased significantly and LV ejection fraction
remained unchanged at the end of the therapy period
compared with pretreatment values.28 In contrast, LV
end-diastolic and end-systolic volume indexes and LV
ejection fraction were unmodified in patients treated
with captopril.28 In patients with mild to moderate heart
failure and average ejection fraction of 25%, the Captopril-Digoxin Multicenter Research Group showed
that compared with placebo, captopril improved exercise time and NYHA classification and reduced the
frequency of ventricular premature beats, whereas
digoxin did not improve exercise time or NYHA classification and slightly increased the frequency of premature ventricular beats.29 In this multicenter study, therapy with digoxin appeared to improve LV ejection
fraction.29 Other studies have suggested that patients
who respond positively to digoxin therapy have more
severe heart failure and greater hemodynamic compromise compared with those who do not respond to
digoxin therapy.30'3' Although unstated, one indirect
implication of these studies is that digoxin therapy may
not be particularly useful in asymptomatic patients with
only moderate LV dysfunction.
The mechanisms through which ACE inhibition,
,3-adrenergic blockade, and digitalis therapy act to
influence the process of progressive LV dysfunction and
dilation in patients or dogs with reduced LV ejection
fraction are not fully understood. Certainly modulation
of afterload must be taken into account when considering potential mechanisms of action of ACE inhibitors.
In the present study, long-term treatment with enalapril
attenuated the progressive rise in systemic vascular
resistance seen in untreated dogs. Enalapril therapy
also prevented the rise in heart rate seen in untreated
dogs and, as such, may have reduced myocardial oxygen
demands. ACE inhibitors also may influence LV function and dilation through mechanisms other than afterload reduction. Such mechanisms include regression of
compensatory hypertrophy,32 reduced accumulation of
collagen in the cardiac extracellular matrix and perivascular space,33'34 and upregulation of cardiac ,B-adrenergic receptors.35 Compensatory hypertrophy of the residual viable myocardium, accumulation of collagen in the
cardiac interstitial compartment, and downregulation of
cardiac P-adrenergic receptors are all characteristic
features of the failing heart and are manifested in the
canine model of heart failure used in this study.14,36
Modulation of afterload also must be considered in the
beneficial effects of 3-blockers in heart failure. In the
present study, long-term metoprolol therapy also attenuated the rise in systemic vascular resistance seen in
untreated dogs. 1-Blockers also have been shown to
increase myocardial 13-adrenoceptor density and improve the contractile response to catecholamine stimulation in patients with heart failure.37 The observed
beneficial effects of metoprolol also may have been
derived in part from improvement in myocardial oxygen
consumption, a feature commonly associated with this
class of drugs.38 In the present study, metoprolol therapy prevented the rise in heart rate and attenuated the
rise in LV wall stress seen in untreated dogs, both of
which are important features that modulate myocardial
oxygen consumption. Although global ischemia,
on myocardial lactate release, does not appear
based
to be
present in the microembolization model of heart failure
used in this study, the presence of ongoing undetectable
focal ischemia cannot be excluded.39 Accordingly, one
cannot exclude the possibility that the observed beneficial effects of metoprolol therapy also could have
resulted in part from an improvement in the coronary
supply-demand balance. Unlike enalapril and metoprolol, digoxin therapy did not impede the process of
progressive LV enlargement. Long-term digoxin therapy had little or no effect on heart rate or systemic
vascular resistance when compared with untreated dogs.
One possible explanation for the seemingly discordant
effect of digoxin on LV systolic function and dilation
may be that digoxin, in this setting, acts primarily as an
inotropic agent, thus helping maintain LV ejection
fraction but not affording substantial protection against
progressive LV dilation.
Conclusions
The results of the present study indicate that in dogs
with reduced LV ejection fraction, early long-term
monotherapy with enalapril or metoprolol prevents the
progressive deterioration of LV systolic function and
arrests or attenuates the process of progressive LV
chamber enlargement. In contrast, early therapy with
digoxin, while preventing the progressive decline in LV
ejection fraction, does not impede the process of progressive LV chamber dilation. Additional investigations
focusing on the morphological, cellular, and biochemical consequences of early therapy with ACE inhibitors,
,8-blockers, or digitalis preparations are needed to gain
further insight into the specific mechanisms of action of
each of these classes of compounds, with respect to their
influence on the process of progressive LV dysfunction
and dilation.
Acknowledgments
This study was supported in part by grants from the American Heart Association of Michigan.
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Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the
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H N Sabbah, H Shimoyama, T Kono, R C Gupta, V G Sharov, G Scicli, T B Levine and S
Goldstein
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Circulation. 1994;89:2852-2859
doi: 10.1161/01.CIR.89.6.2852
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