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431
Effects of the Angiotensin Converting Enzyme
Inhibitor Enalapril on the Long-term
Progression of Left Ventricular Dysfunction
in Patients With Heart Failure
Marvin A. Konstam, MD; Michel F. Rousseau, MD; Marvin W. Kronenberg, MD;
James E. Udelson, MD; Jacques Melin, MD; Dawn Stewart, MS; Noreen Dolan, RN;
Tonya R. Edens, RN; Sylvie Ahn; Debra Kinan, RT(N); Donna M. Howe, RN;
Lori Kilcoyne, RN; Jeanne Metherall, RT(N); Claude Benedict, MD;
Salim Yusuf, MRCP, DPhil; and Hubert Pouleur, MD, for the SOLVD Investigators
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
Background. In patients with heart failure, activation of the renin-angiotensin system is common and
has been postulated to provide a stimulus for further left ventricular (LV) structural and functional
derangement. We tested the hypothesis that chronic administration of the angiotensin converting enzyme
(ACE) inhibitor enalapril prevents or reverses LV dilatation and systolic dysfunction among patients with
depressed ejection fraction (EF) and symptomatic heart failure.
Methods and Results. We examined subsets of patients enrolled in the Treatment Trial of Studies of Left
Ventricular Dysfunction (SOLVD). Fifty-six patients with mild to moderate heart failure underwent serial
radionuclide ventriculograms, and 16 underwent serial left heart catheterizations, before and after
randomization to enalapril (2.5-20 mg/day) or placebo. At 1 year, there were significant treatment
differences in LV end-diastolic volume (EDV; p<0.01), end-systolic volume (ESV; p<0.005), and EF
(p<0.05). These effects resulted from increases in EDV (mean±+SD, 136±27 to 151+±38 ml/m2) and ESV
(103±24 to 116±24 ml/m2) in the placebo group and decreases in EDV (140±44 to 127±37 ml/m2) and
ESV (106±42 to 93+±37 ml/m2) in the enalapril group. Mean LVEF increased in enalapril patients from
0.25±0.07 to 0.29±0.08 (p<0.01). There was a significant treatment difference in LV end-diastolic
pressure at 1 year (p<0.05), with changes paralleling those of EDV. The time constant of LV relaxation
changed only in the placebo group (p<0.01 versus enalapril), increasing from 59.2±8.0 to 67.8+7.2 msec.
Serial radionuclide studies over a period of 33 months showed increases in LV volumes only in the placebo
group. Two weeks after withdrawal of enalapril, EDV and ESV increased to baseline levels but not to the
higher levels observed with placebo.
Conclusions. In patients with heart failure and reduced LVEF, chronic ACE inhibition with enalapril
prevents progressive LV dilatation and systolic dysfunction (increased ESV). These effects probably result
from a combination of altered remodeling and sustained reduction in preload and afterload. (Circulation
1992;86:431-438)
KEY WoRDs * vasodilation
*
ventricular function
*
cardiomyopathies
*
ejection fraction
eeart failure caused by left ventricular (LV)
systolic dysfunction is characterized by progressive symptomatic deterioration and high
mortality.'-3 Angiotensin converting enzyme (ACE)
inhibitors improve exercise capacity in patients with
heart failure4-9 and improve survival in patients who are
severely symptomatic (New York Heart Association
[NYHA] class IV).10 The Studies of Left Ventricular
Dysfunction (SOLVD) include two large-scale, randomized, placebo-controlled trials designed to assess the
effect of the ACE inhibitor enalapril on survival in
patients with depressed LV ejection fraction (.0.35).
The recently reported results of the SOLVD Treatment
Trial1' indicated a significant reduction in mortality by
enalapril in patients with symptomatic heart failure,
most of whom were in NYHA class II or III, over a
mean follow-up of 42 months.
From the Departments of Medicine and Radiology (M.A.K.,
J.E.U., N.D., D.K., L.K., J.Metherall), Tufts University, New
England Medical Center, Boston; Divisions of Cardiology and
Nuclear Medicine (M.F.R., J.Melin, S.A., H.P.), University of
Louvain School of Medicine, Brussels; Departments of Medicine
and Radiology (M.W.K., T.R.E., D.M.H.), Vanderbilt University
School of Medicine, Nashville, Tenn.; Collaborative Studies Coordinating Center, Department of Biostatistics (D.S.), University
of North Carolina, Chapel Hill; Department of Medicine (C.B.),
University of Texas Health Science Center, Houston; and the
Clinical Trials Branch (S.Y.), National Heart, Lung, and Blood
Institute, Bethesda, Md.
Supported by National Heart, Lung, and Blood Institute contract N01-HC55010, National Institutes of Health, Bethesda, Md.
Address for correspondence: Marvin A. Konstam, MD, Box 108,
New England Medical Center, 750 Washington Street, Boston,
H
MA 02111.
Received February 14, 1992; revision accepted May 6, 1992.
432
Circulation Vol 86, No 2 August 1992
To examine the natural history of LV volume and
function and the effects of chronic ACE inhibition on
this course, we performed serial radionuclide ventriculograms and serial cardiac catheterizations in subsets of
patients enrolled in the SOLVD Treatment Trial and
randomized to receive either enalapril or placebo. We
postulated that patients with symptomatic heart failure
are characterized by progressive LV dilatation and
systolic dysfunction and that this course is prevented or
reversed by chronic therapy with an ACE inhibitor.
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Methods
Study Protocol
Fifty-six patients participating in the SOLVD Treatment Trial at three centers who also consented to
participate in the substudy were enrolled in the radionuclide study between September 1987 and March 1991.
Participating centers were Tufts University/New England Medical Center, Boston; Vanderbilt University,
Nashville, Tenn.; and the University of Louvain, Brussels. Sixteen Treatment Trial patients at the University
of Louvain (including 14 patients participating in the
radionuclide study) were enrolled in the catheterization
study. Radionuclide and catheterization protocols were
approved by the Human Investigation Review Committees at each institution at which they were performed,
and all patients gave written informed consent. Radionuclide and catheterization studies were performed
before randomization and 1 year after randomization.
At Tufts University and Vanderbilt University, radionuclide studies were performed at three additional time
points: 1) 4 months after randomization; 2) at the
completion of SOLVD, 20-36 (mean 33) months after
randomization, while patients continued to receive the
study drug; and 3) after withdrawal of the study drug for
an average of 15 days at the completion of SOLVD.
Enrollment criteria were that LV ejection fraction,
measured within the preceding 3 months, be <0.35 and
that patients be receiving medication for treatment of
symptomatic heart failure.1112 Patients were excluded if
any of the following were present: age >80 years,
hemodynamically significant valvular disease requiring
surgery, unstable angina, angina thought to be severe
enough to require revascularization procedures, myocardial infarction within the previous 30 days, severe
pulmonary disease, serum creatinine > 2 mg/dl, or other
diseases that might significantly shorten survival or
impair participation in a long-term trial. Before baseline
measurements, all patients received single-blind enalapril, 2.5 mg orally twice daily, for 2-7 days to screen for
intolerance to this lowest dosage, followed by singleblind placebo for 14 to 17 days to screen for noncompliance or worsening of clinical condition upon drug
withdrawal.
After initial baseline radionuclide and catheterization
measurements, patients were randomized to receive
either placebo or enalapril, 5 mg orally twice daily. The
drug dosage was increased to 10 mg twice daily if
tolerated or decreased if necessitated by adverse effect.
Radionuclide and catheterization studies were performed with the patient supine for at least 30 minutes
after an overnight fast. Diuretics and non-ACE inhibitor vasodilators were withheld for a minimum of 12 and
4 hours, respectively. All studies except before random-
ization and after withdrawal were performed 2-6 hours
after a dose of the study drug.
Radionuclide Studies
Red blood cells were labeled by a modified in vivo
method as previously described.13 Equilibrium-gated
radionuclide ventriculograms were acquired in a modified left anterior oblique projection with caudal angulation.14-'6 Scans were acquired for 8 minutes (minimum
5 million counts), with each cardiac cycle divided into 32
frames. Blood pressure was recorded with a sphygmomanometer at least twice during the course of the scan
acquisition, and the recordings were averaged.
Radionuclide studies were analyzed at the SOLVD
Radionuclide/Ventricular Performance Core Laboratory at Tufts University/New England Medical Center
by previously described techniques.14-17 Studies were
analyzed and reviewed by a technologist and a physician
who were blinded to treatment. LV end-diastolic and
end-systolic volumes were calculated on the basis of the
ratio of background-subtracted LV counts to counts
within a 5-ml blood sample, corrected for tissue attenuation.17 LV stroke volume was calculated as end-diastolic volume minus end-systolic volume, LV output was
calculated as stroke volume times heart rate, and ejection fraction was calculated as stroke volume divided by
end-diastolic volume.
We tested intraobserver variability of our radionuclide measurements by analysis of duplicate scans with
duplicate blood sample acquisitions in a series of 10
patients. Coefficients of variation were as follows: LV
ejection fraction, 3.9% (percent of measured ejection
fraction) and LV end-diastolic and end-systolic volumes, 3.4% and 3.1%, respectively. In all cases, the
correlation coefficient between duplicate measurements
was 0.99.
Catheterization
Left heart catheterization was performed without
premedication, as described previously.'8 An 8F pigtail
Millar catheter (Millar Instruments Inc., Houston, Tex.)
was introduced through the femoral artery to measure
high-fidelity LV pressure and to inject contrast material. Angiographic images were acquired with Philips
Polydiagnost C and DVI systems (Philips Instruments,
Best, The Netherlands). These systems allow the acquisition of nonsubtracted LV images at 50 frames per
second with 1,024 shades of gray (10 bits) and a
geometric resolution of approximately 0.7 mm. During
the 3 msec of frame exposure, there was simultaneous
acquisition of the LV pressure and the ECG signal.19
LV pressure, together with the ECG signal, was continuously recorded on analog magnetic tape (Honeywell
101, Honeywell Information Systems, Inc., Waltham,
Mass.).
Hemodynamic and Ventriculographic Data Analysis
One patient who had been randomized to enalapril
was excluded from analysis because a severely abnormal
LV contour precluded accurate assessment of ventricular volumes. In the remaining patients, analog data were
digitized every 2 msec and processed off-line with a
Hewlett-Packard A900 computer (Hewlett-Packard
Co., Palo Alto, Calif.). Specific points of the signals
(such as the peak of the R wave or the LV end-diastolic
Konstam et al Enalapril Effect on Ventricular Function
pressure) were automatically detected by a set of subroutines for generation of average pressure-volume
loops.19 LV pressure data after peak negative dP/dt
were also fitted to an exponential relation by a leastsquares regression technique, and the time constant T1
(0-40 msec after peak negative dP/dt) of this relation
used as an index of LV isovolumic relaxation.20
Peak positive dP/dt and the dP/dt measured and normalized at a developed pressure of 40 mm Hg, (dP/dt)/
DP40,21 were used as isovolumic indexes of inotropic
state. For evaluation of LV function, masked ventricular
silhouettes were outlined frame by frame on a video
screen with an electronic cursor. Both premature and
postpremature beats were excluded from analysis. A
computer system (APU Philips, Philips Electronic Instruments Co., Mahwah, N.J.) was used to derive the
correction factor for x-ray magnification and calculated
volumes every 20 msec by applying Simpson's rule. The
ejection fraction was calculated using the frame with the
maximal pressure-volume ratio as end systole.22,23 The
was
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LV pressure-volume loop was constructed after data
smoothing for each patient, and the individual loops
were averaged by the method described previously.19
The angiographic data were analyzed by two blinded
observers.
Plasma Renin Assay
Blood samples were drawn via an indwelling intraveline, with the patient supine for at least 30
minutes. Plasma samples were shipped on dry ice and
were analyzed at the SOLVD Neuroendocrine Core
Laboratory at the University of Texas Health Science
Center, Houston. Plasma renin activity was measured
by radioimmunoassay.24,25
nous
Statistics
Statistical analyses were performed at the Collaborative Studies Coordinating Center, University of North
Carolina. All data were analyzed according to intention
to treat and were adjusted for center variations. The
primary analysis examined group means and treatment
effects among patients who underwent study both before randomization and at 1 year. In addition, attempts
were made to identify potential biases resulting from
patient death or dropout. For this purpose, imputation
of data was performed by three methods: 1) use of last
available data, 2) linear regression applied to all available data from the individual patients, and 3) rank
observations, assigning the worst ranks to patients who
died soonest. All treatment effects remained consistent
regardless of analysis strategy. The significance of
changes from baseline in each parameter within each
treatment group was analyzed by paired t test. Significance of treatment effect (enalapril group versus placebo group) was determined by ANCOVA, adjusting
for baseline values, for radionuclide measurements, and
by unpaired t test for catheterization study parameters.
Repeated-measures analysis was performed to examine
treatment differences across the five sets of measurements performed at two study sites.
Results
Of the 56 patients entered into the radionuclide
study, 31 were randomized to receive enalapril and 25 to
receive placebo. Two patients randomized to enalapril
433
TABLE 1. Baseline Characteristics
Baseline
Baseline and
study only
1-year studies
(dropouts)
Enalapril Placebo Enalapril Placebo
(n=24) (n=15) (n=7*) (n =l10)
Age (years; mean+SD)
59±7
63±9
57±10 62±13
Males (%)
79
73
86
50
Cause (%)
79
73
71
70
Coronary disease
21
27
29
30
Idiopathic
NYHA class (%)
8
7
0
0
II
67
43
80
70
III
25
13
57
30
Iv
0
0
0
0
Medications (%)
Digoxin
46
47
71
70
Diuretics§
79
60
71
90
-
Vasodilators§
(non-ACE inhibitors)
67
57
75
80
EF (%; mean±'SD)
25±7
25±5
25±7
26±8
NYHA, New York Heart Association; ACE, angiotensin converting enzyme; EF, ejection fraction.
*Two deaths, four refusals, one cardiac transplant. tSeven
deaths, three refusals. tWith previous clinical evidence of heart
failure. §Withheld before each radionuclide and catheterization
study.
and seven randomized to placebo died before 1 year.
Five additional enalapril patients (four refusals, one
cardiac transplant) and three additional placebo patients (refusals) failed to undergo repeat radionuclide
study at 1 year. Therefore, the primary analysis of
enalapril effect on radionuclide-derived parameters at 1
year comprised data from 39 patients, 24 randomized to
enalapril and 15 to placebo. The study drug had been
discontinued in one of the 24 enalapril patients studied
at 1 year. None of the 15 placebo patients were receiving
an ACE inhibitor. Of patients randomized to enalapril,
the mean study drug dose was 15.7 mg/day; it was 16.4
mg/day for patients continuing to take the study drug.
Table 1 lists clinical characteristics of the study
population at baseline, comparing findings between the
enalapril and placebo groups for the 39 patients who
contributed to the 1-year radionuclide analysis and the
17 who did not. There were no significant differences
between enalapril and placebo groups for any baseline
characteristic. Patients who were not studied at 1 year
appeared slightly sicker at baseline, with a higher proportion of patients in NYHA class III and a higher
proportion receiving digoxin. However, none of these
differences were statistically significant, and these characteristics were similar in groups randomized to enalapril and to placebo.
Heart rate, blood pressure, and radionuclide-derived
parameters measured before randomization and 1 year
after randomization to either placebo or enalapril are
listed in Table 2. There was no difference between
enalapril and placebo groups with regard to any parameter at baseline. At 1 year, both systolic and diastolic
blood pressure were reduced compared with baseline in
434
Circulation Vol 86, No 2 August 1992
TABLE 2. Results: Heart Rate, Blood Pressure, and Radionuclide Measurements
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p
p
Baseline
1 year
(B vs. 1 year)
(P vs. E*)
74+6
p
78+11
Heart rate (min-1)
NS
77±14
E
0.01
68±12
0.04
129±17
125±12
p
NS
Systolic BP (mm Hg)
E
130±25
122±19
0.05
NS
p
78±10
78±7
NS
Diastolic BP (mm Hg)
E
76±11
0.05
72±9
NS
p
LVEDV (mlm2)
136±27
0.10
151±38
E
140±44
127±37
0.02
0.008
p
103±24
116±24
LVESV (m1/M2)
0.08
E
106±42
0.01
93±37
0.002
P
25+5
NS
24+8
LVEF (%)
E
25+7
0.01
29+8
0.04
P
33+8
NS
35-+±12
LVSV (ml/m2)
E
33+8
NS
34±8
NS
p
2.5+0.6
NS
2.6±0.9
LVCO (1/min/m2)
2.5±0.6
NS
2.3±0.6
E
NS
B, baseline; P, placebo; E, enalapril; BP, blood pressure; LV, left ventricular; EDV, end-diastolic
volume; ESV, end-systolic volume; EF, ejection fraction; SV, stroke volume; CO, cardiac output. Data
are mean±SD. P, n=15; E, n=24.
*Significance for difference in treatment effect.
enalapril-treated patients. Heart rate was significantly
reduced at 1 year in the enalapril group, and the
difference between the two groups with regard to heart
rate change was statistically significant.
The enalapril and placebo groups differed significantly in terms of change in LV end-diastolic volume
and end-systolic volume, with ventricular volumes increasing in the placebo group and decreasing in the
enalapril group. The groups also differed with regard to
change in ejection fraction, which increased compared
with baseline in enalapril-treated patients but not in
placebo-treated patients. There were no significant differences between the two patient groups with regard to
change in LV stroke volume or LV minute output.
Of patients undergoing catheterization before randomization, two placebo patients died and one enalapril
patient underwent cardiac transplant before one year.
One additional enalapril patient refused repeat catheterization. Of the 11 patients who underwent repeat
catheterization at 1 year, six had been randomized to
enalapril and five to placebo. Data derived during
catheterization performed before randomization and 1
year after randomization are presented in Table 3.
Changes in ventricular volumes were consistent with
radionuclide findings. In addition, the two groups differed significantly in terms of treatment effect on LV
end-diastolic pressure, with changes paralleling those in
end-diastolic volume. Isovolumic indexes of contractility trended downward in the placebo group, with statistical significance reached for peak positive dP/dt, although these changes were not significantly different
from those observed in the enalapril group. In contrast,
changes from baseline to 1 year in the time constant of
relaxation differed significantly between the two patient
groups, increasing in the placebo group and remaining
unchanged in the enalapril group.
Figure 1 depicts the average LV pressure-volume
loops at baseline and at 1 year for patients randomized
to placebo and to enalapril. The entire curve was shifted
rightward in the placebo group and leftward in the
enalapril group. There was no obvious upward or downward displacement or alteration in the slope of the
curve during diastole.
Figure 2 shows radionuclide findings and systolic
blood pressure before randomization; at 4 months, 1
year, and an average of 33 months after randomization;
and an average of 15 days after withdrawal from enalapril (n = 11) or placebo (n=7) from the two centers at
which these multiple time points were sampled. Repeated-measures analyses revealed significant treatment differences in both end-diastolic (p<0.05) and end-systolic
volumes (p<0.05) with either exclusion or inclusion of
postwithdrawal data points. Progressive increases from
baseline in LV volumes in the placebo group and an
early and sustained reduction in LV volumes in the
enalapril group contributed to these treatment differences. After withdrawal from enalapril, both systolic
blood pressure and LV volumes increased to approximately the level observed before randomization. However, ventricular volumes did not reach the higher levels
observed in the placebo group. Measurements of
plasma renin activity indicated that ACE inhibitor
effect had been removed after withdrawal of enalapril.
In the enalapril group, plasma renin activity increased
from 2.2+1.6 ng/ml/hr at baseline to 11.7±13.7 ng/
ml/hr (p<O.OS) just before drug withdrawal. This value
decreased to 1.4±+1.4 ng/ml/hr at the time of the
postwithdrawal radionuclide study (not significantly different compared with baseline). In placebo patients,
plasma renin activity did not change significantly during
the study period.
Between 11 and 19 days after withdrawal from the
study drug at the completion of SOLVD, four patients,
all of whom had been withdrawn from enalapril, developed adverse events. Of these, two patients suffered
myocardial infarction, and one of these two developed
Konstam et al Enalapril Effect on Ventricular Function
435
TABLE 3. Catheterization Results
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P
p
Baseline
1 year
(B vs. 1 year)
(P vs. E*)
P
LVEDV (ml/m2)
185±53
200±41
NS
E
193±38
180±42
0.03
0.06
LVESV (ml/m')
P
149±41
167±54
NS
E
152±35
133±38
0.03
0.04
LVEF(%)
P
19±5
18±3
NS
E
21±9
27±5
NS
NS
P
LVEDP (mm Hg)
25±9
30±5
NS
E
30±10
23±7
0.04
0.02
P
LVSP (mm Hg)
123±28
128±15
NS
E
133±35
131±14
NS
NS
P
Peak positive dP/dt (mm Hg/sec)
1,196±269
1,021±214
0.05
E
1,328±705
1,116±318
NS
NS
P
(dP/dt)/DP40 (sec-')
15.2±6.2
13.0±3.1
NS
E
17.3±10.8
16.5±6.5
NS
NS
P
T1 (msec)
59.2±8.0
67.8±7.2
0.0001
E
62.0± 10.6
62.0±8.0
NS
0.01
B, baseline; P, placebo; LV, left ventricular; EDV, end-diastolic volume; ESV, end-systolic volume; EF, ejection
fraction; EDP, end-diastolic pressure; SP, peak systolic pressure; dP/dt, rate of LV pressure change; DP40, at developed
pressure of 40 mm Hg; T1, time constant of early relaxation. Data are mean± SD. P, n=5; E, n=6.
*Significance for difference in treatment effect.
cardiogenic shock and died. One patient developed
unstable angina and underwent emergency coronary
artery bypass graft surgery. One patient was hospitalized with ventricular tachycardia and worsening heart
failure and subsequently died.
A
PLACEBO
nn,
BASELINE
1
YEAR
m
E
100-
cD
E
50 -
W
en
n=5
o0
,
.
100 120 140 160 180 200
1
120 .
1
VOLUME (ml/m2)
E
U)
B
W
1
nu
a.
I
ENALAPRIL
.
1 YEAR
BASELINE
B 100w
CD
tn
cc
50n=6
n
100 120 140 160 180 200
VOLUME (milm2)
FIGURE 1. Mean left ventricular pressure-volume loops at
baseline and 1 year in patients randomized to placebo (panel
A) and to enalapril (panel B). At 1 year, the entire curve was
shifted to the right for the placebo group and to the left for the
enalapril group.
Discussion
Activation of the renin-angiotensin-aldosterone axis
in patients with heart failure provides rationale for the
therapeutic use of ACE inhibitors.25 ACE inhibitors have
been documented to improve hemodynamics acutely and
functional capacity chronically in patients with heart
failure caused by LV systolic dysfunction.4-9,26 Two largescale placebo-controlled trials have documented that the
ACE inhibitor enalapril improves survival in patients
with NYHA functional class IV10 and class 11-III heart
failure.'1 In both of these studies, enalapril-induced
improvement in survival resulted principally from a reduction in mortality related to worsening heart failure. In
addition, enalapril was found to reduce the frequency of
hospitalization for worsening heart failure." In the present study, we observed that chronic ACE inhibition
substantially improved the natural history of changes in
LV cavity size and mechanical performance in patients
with mild to moderate heart failure caused by LV systolic
dysfunction. It is tempting to speculate that the beneficial
effects of enalapril on ventricular dilatation and performance are related to the reduction in the clinical expression and mortality of heart failure.'0"11
Ventricular remodeling has been best described in
the setting of prior myocardial infarction.27 33 After
myocardial infarction, the LV cavity dilates because of
thinning and expansion within the infarcted zone.27,29,30
Subsequent LV dilatation appears to be related to
hypertrophy with expansion of the endocardial surface
in noninfarcted regions.3031 Several studies have suggested that inhibition of the renin-angiotensin system
may reduce the propensity to myocardial hypertrophy
and remodeling after acute myocardial infarction, possibly through vasodilation and reduction in myocardial
wall stress.33-37 In all of these studies, ACE inhibition
was initiated early after myocardial infarction.
Our study population comprised patients with clinical
heart failure caused by coronary artery disease or
436
Circulation Vol 86, No 2 August 1992
A END-DIASTOLIC VOLUME
170
1
PLACEBO
150
ml/m2
ENALAPRIL
130-
110
BASE
4mo
lyr
33mo
WD
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END-SYSTOLIC VOLUME
B
i,n -.
*_4v
SBP (mmHg +1- SE):
c
130
132
128
130
132
(7)
(6)
(5)
(5)
m7
PLACEBO
120mi/m2
100
1 ~
-
130
80
(10)
BASE
~~~~~~~
[p'0-03 1 .
'.
118
(7
120
11(6
130
(5)
(6)
(8)
4mo
lyr
33mo
WD
dilated cardiomyopathy, with specific exclusion of patients with recent myocardial infarction. Our findings,
therefore, support the concept that the LV protective
effect of chronic ACE inhibition is not confined to
patients with coronary disease or to those with recent
myocardial infarction. Rather, it is likely that LV remodeling is a chronic, progressive process that continues after the clinical expression of heart failure and
occurs regardless of the primary cause of myocardial
disease. This process may be slowed or reversed by ACE
inhibitor therapy, even if instituted at a time remote
from that of the initial insult. Return of LV volumes to
baseline levels after withdrawal of enalapril indicates
that a component of ACE inhibitor effect results from
an ongoing influence on ventricular load. LV volumes
did not reach the higher levels observed within the
placebo group, however. The latter finding supports the
view that enalapril altered the progression of ventricular
remodeling.
Within our placebo group, the rate of isovolumic LV
pressure rise decreased significantly at 1 year, suggesting
further depression in contractility, although the differ-
FIGURE 2. Graphs of left ventricular end-diastolic (panel A) and end-systolic (panel B) volumes (mean+±SEM) for enalapril and placebo
groups at baseline (BASE); at 4 months, 1 year,
and 20-36 (mean 33) months after randomization; and 2 weeks after withdrawal (WD) ofstudy
drug. Also listed are average (±SEM) systolic
blood pressures (SBP) for each group at each time
point. Placebo-treatedpatients manifested progressive increases in ventricular volumes, whereas
enalapril-treated patients showed an early and
sustained reduction in LV volumes and blood
pressure. After withdrawal of enalapril, in association with a return to baseline blood pressure, LV
volumes increased to approximately baseline levels
but remained below those of the placebo group.
Probability values are derived from repeated-measures analyses, examining treatment differences
across the first four sets of data points. Differences
remained significant (p<0.05) with inclusion of
postwithdrawal data.
ENALAPRIL
ence between the two patient groups in terms of the
change in this parameter was not statistically significant.
However, the ventricular pressure-volume curves
showed a rightward shift at end systole in placebo-treated
patients, which was opposite to that seen in the enalapril
group, suggesting that enalapril prevented or reversed
progression of myocardial contractile dysfunction.
Changes in end-diastolic pressure paralleled changes
in end-diastolic volume in a manner that could represent movement along a fairly constant diastolic pressure-volume curve. There was a significant difference in
change in the time constant of relaxation between the
enalapril and placebo groups, however, with the latter
group manifesting progressive aberration in myocardial
relaxation. It cannot be determined whether this difference is independent of differences in load and in
end-systolic volume between the two groups.
We are uncertain about the relation between enalapril withdrawal and the adverse events observed after
discontinuation of the study drug. Within the SOLVD
Treatment Trial, a reduction in the incidence of fatal
myocardial infarction contributed to the reduction in
Konstam et al Enalapril Effect on Ventricular Function
mortality among patients randomized to enalapril.11
Recently, levels of plasma renin activity have been
found to be related to the incidence of myocardial
ischemic events independently of the degree of hypertension.38 The events in our patients raise the possibility
that abrupt withdrawal of enalapril, through undefined
mechanisms, results in acute myocardial ischemia, perhaps mediated through increased levels of angiotensin
II.
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In summary, long-term enalapril administration to
patients with symptomatic LV systolic dysfunction results in favorable changes in ventricular volumes that
are significantly different from the progressive dilatation
observed in placebo-treated controls. These differences
are likely to result both from prevention of adverse
ventricular remodeling and from ongoing effects on
ventricular systolic and diastolic load. Additional investigation is needed to gain further insight into the
mechanisms by which ACE inhibition achieves these
effects and into the relation among the effects of ACE
inhibitors on ventricular performance, symptoms, functional capacity, and survival.
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Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term
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Circulation. 1992;86:431-438
doi: 10.1161/01.CIR.86.2.431
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