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2277
Effects of the Angiotensin Converting Enzyme
Inhibitor Enalapril on the Long-term
Progression of Left Ventricular
Dilatation in Patients With
Asymptomatic Systolic Dysfunction
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Marvin A. Konstam, MD; Marvin W. Kronenberg, MD; Michel F. Rousseau, 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, FRCP, DPhil; Hubert Pouleur, MD; for the SOLVD Investigators
Background. Patients with heart failure and reduced left ventricular (LV) ejection fraction (EF) manifest
progressive LV dilatation, which is prevented by angiotensin converting enzyme (ACE) inhibitors. In
patients with asymptomatic LV systolic dysfunction, in whom there is less activation of the renin-angiotensin
system, ventricular remodeling might be less rapid and the benefit of ACE inhibitors less discernible.
Methods and Results. One hundred eight patients enrolled in the Studies of Left Ventricular Dysfunction
(SOLVD) Prevention Trial, with left ventricular ejection fraction <0.35 but without clinical heart failure,
underwent radionuclide ventriculograms, and 49 underwent left heart catheterizations. Measurements
were made before and after double-blinded randomization to enalapril (2.5 to 20 mg/d) or placebo.
Repeated-measures analysis of all time points showed significant differences for change in end-diastolic
volume (EDV) between enalapril and placebo groups. Significant difference between the enalapril and
placebo groups (P<.05) was present for change in EDV at 1 year within the catheterization study and at
a mean of 25 months within the radionuclide study. Radionuclide EDV increased in placebo patients
(119±28 to 124±33 mlm2, mean+SD) and decreased in enalapril patients (120±25 to 113±25 mLum2).
Differences between the two groups were significantly less than previously described in patients with
symptomatic heart failure (P<.02), with less increase in LV volumes in the placebo group and less
decrease in volumes in the enalapril group.
Conclusions. Chronic ACE inhibitor treatment slows or reverses LV dilatation in patients with
asymptomatic LV systolic dysfunction. Compared with symptomatic patients, asymptomatic patients
manifest a slower rate of spontaneous LV dilatation and less reduction in LV volumes by enalapril.
(Circulation. 1993;88[part 11:2277-2283.)
KEY WoRDS * vasodilation * ejection fraction * heart failure
Patients with depressed left ventricular (LV) ejection fraction manifest progressive LV dilatation
and systolic functional impairment, findings that
have been attributed to excessive wall stress.12 We
Received March 30, 1993; revision accepted July 7, 1993.
From the Departments of Medicine and Radiology (M.A.K.,
J.E.U., N.D., D.K., L.K., J.M.), Tufts University, New England
Medical Center, Boston; the Departments of Medicine and Radiology (M.W.K., T.R.E., D.M.H.), Vanderbilt University School of
Medicine, Nashville, Tenn; the Divisions of Cardiology and Nuclear Medicine (M.F.R., J.M., S.A., H.P.), University of Louvain
School of Medicine, Brussels, Belgium; the Collaborative Studies
Coordinating Center (D.S.), Department of Biostatistics, University of North Carolina, Chapel Hill; the 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.
Correspondence to Marvin A. Konstam, MD, Box 108, New
England Medical Center, 750 Washington St, Boston, MA 02111.
previously observed that this adverse progression may
be halted by chronic administration of angiotensin
converting enzyme (ACE) inhibitors.2 The relative degree to which LV dilatation and systolic dysfunction
progresses and the relative benefit of ACE inhibition in
patients with symptomatic versus asymptomatic depression of LV ejection fraction has not been explored.
Asymptomatic patients manifest less or absent elevations in plasma renin,3 and this difference may result in
less rapid alteration in myocardial architecture and
function. Furthermore, it might imply that less benefit is
derived from administration of ACE inhibitors in such
patients.
In the present study, we performed serial radionuclide measurements of LV volumes and function over an
average of 25 months in patients enrolled in the Prevention Trial of Studies of Left Ventricular Dysfunction
(SOLVD), who were randomized to long-term enalapril
2278
Circulation Vol 88, No 5, Part 1 November 1993
or placebo. In this asymptomatic population with LV
ejection fractions .0.35, we explored the rate of enlargement of ventricular volumes and the influence of
ACE inhibitor treatment on ventricular dilatation.
Methods
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Study Protocol
The radionuclide study population consisted of 108
patients participating in the SOLVD Prevention Trial at
three centers: Tufts University, New England Medical
Center, Boston; Vanderbilt University, Nashville, Tenn;
and University of Louvain, Brussels, Belgium. At the
University of Louvain, 49 prevention trial patients (including 40 patients participating in the radionuclide
study) were enrolled in the catheterization study. Both
radionuclide and catheterization studies were performed before randomization and 1 year after randomization. At Tufts University and at Vanderbilt University, radionuclide studies were performed at three
additional time points: (1) 4 months after randomization; (2) at the completion of SOLVD, 13 to 45 months
(mean, 25) after randomization while patients continued to receive study drug; (3) after withdrawal of study
drug for a minimum of 5 days, at the completion of
SOLVD. 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.
Entrance criteria for the prevention trial included LV
ejection fraction <0.35 measured within the preceding 3
months by radionuclide ventriculography, echocardiography, or contrast ventriculography and absence of
medication prescribed for treatment of heart failure.4'5
The protocol permitted use of digitalis if prescribed for
supraventricular arrhythmia, diuretics, or vasodilators if
prescribed for hypertension and nitrates if prescribed
for angina. This population differed from that of the
previously reported treatment trial,2 in whom treatment
for heart failure was considered indicated. Patients
were excluded if any of the following were present: age
greater than 80 years, hemodynamically significant valvular disease requiring surgery, unstable angina, angina
thought to be severe enough to require revascularization, 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 singleblind enalapril, 2.5 mg orally, twice daily, for 2 to 7 days
to screen for intolerance to this lowest dose, followed by
single-blind 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) twice daily, orally.
The drug dose 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 prerandomiza-
tion and postwithdrawal were performed 2 to 6 hours
after a dose of study drug.
Radionuclide Studies
Red blood cells were labeled by a modified in vivo
method, as previously described.6 Equilibrium-gated
radionuclide ventriculograms were acquired in a modified left anterior oblique projection with caudal angulation.7-9 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,
using previously described techniques.7-10 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 based on the ratio
of background-subtracted LV counts to counts within a
5-mL blood sample, corrected for tissue attenuations
LV stroke volume was calculated as end-diastolic volume minus end-systolic volume, LV output as stroke
volume times heart rate, and ejection fraction as stroke
volume divided by end-diastolic volume.
We previously 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); LV end-diastolic and endsystolic 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." 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/s with
1024 shades of gray (10 bits) and a geometric resolution
of approximately 0.7 mm. During the 3 milliseconds of
frame exposure, there was simultaneous acquisition of
the LV pressure and the ECG signal.'2 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
Analog data were digitized every 2 milliseconds and
processed off-line by means of 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 pressure, LVEDP) were automatically detected by a set of subroutines for generation
of average pressure-volume loops.'2 The angiographic
data were analyzed by two blinded observers. Masked
ventricular silhouettes
a
video
screen
were
outlined frame by frame
on
using an electronic cursor. Both prema-
Konstam et al Enalapril Effect on Ventricular Dilatation
ture and postpremature beats were excluded from analysis. A computer system (APU Philips, Philips Electronic Instrument Co, Mahwah, NJ) was used to derive
the correction factor for x-ray magnification and calculated volumes every 20 milliseconds by applying Simpson's rule. The LV pressure-volume loop was constructed after data smoothing for each patient, and the
individual loops were averaged using the method described previously.12
Plasma Renin Assay
With the patient supine for at least 30 minutes, blood
samples were drawn via an indwelling intravenous line
into a tube containing sodium-EDTA. Plasma samples
were shipped on dry ice and were analyzed at the
SOLVD Neuroendocrine Core Laboratory at the University of Texas, Galveston, later relocated to the
University of Texas Health Science Center, Houston.
Plasma renin activity was measured using a standard
radioimmunoassay.3
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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. Results
are expressed as mean ±SD. Significance of change from
baseline in each parameter within each treatment group
was analyzed using paired t tests. Significance of treatment effect (enalapril group vs placebo group) and of
between-trial (prevention trial vs treatment trial) comparisons was determined by analyses of covariance,
adjusting for baseline values. Repeated-measures analysis was performed to examine treatment differences
across the multiple sets of measurements performed at
two study sites.
Results
Of the 108 patients entered into the radionuclide
study, 53 were randomized to receive enalapril and 55 to
receive placebo. Of the 49 patients entered into the
catheterization study (including 40 enrolled in the radionuclide study), 27 were randomized to enalapril and
22 to placebo. Five enalapril patients and 4 placebo
patients died before 1 year (4 enalapril and 3 placebo
patients within the catheterization study). Six additional
enalapril patients (5 refusals, 1 intercurrent coronary
bypass surgery) and 7 additional placebo patients (3
refusals, 2 heart transplants, 2 coronary bypass surgery)
did not undergo repeat radionuclide study at 1 year (4
enalapril and 9 placebo patients within the catheterization study). Thus, 86 patients (42 enalapril and 44
placebo) had radionuclide studies, and 29 patients (19
enalapril and 10 placebo) had catheterizations performed at baseline and 1 year and were included in the
analysis.
In 1 of the 42 enalapril patients (none within the
catheterization study), study drug had been discontinued because of adverse effect; the remainder were
receiving active study drug. In 4 of the 44 placebo
patients, study drug had been discontinued (none within
the catheterization study): In 2 patients, adverse effects
had occurred, and in 2 patients, open-label ACE inhibitor had been instituted because of clinical deterioration. At 1 year, the mean study drug dose was 17.9 mg/d
2279
TABLE 1. Baseline Characteristics
Mean age, y
Men, %
Etiology, %
Coronary disease
Dilated cardiomyopathy
Medications, %
Digoxint
Diureticst§
Vasodilators§II
(non-ACE inhibitors)
EF, % (mean±SD)
Radlonucilde
Catheterization
Study (n=108*)
Study (n=49)
Enalapril Placebo Enalapril Placebo
(n=53) (n=55) (n=27) (n=22)
57
55
58
58
82
93
93
91
87
13
84
16
85
15
91
9
13
6
40
9
7
40
0
0
44
0
0
41
30±6
29±7
29±4
28±7
ACE indicates angiotensin converting enzyme and EF, ejection fraction.
*Includes 40 patients participating in the catheterization study;
tfor supraventricular arrhythmia; *for hypertension; §withheld
before each radionuclide and catheterization study; INor hypertension or angina.
among patients randomized to enalapril and 18.6 mg/d
for patients continuing to take study drug. Corresponding doses for patients randomized to placebo were 15.2
and 18.0 mg/d, respectively.
Sixty-eight patients were enrolled at the two centers
that performed radionuclide studies at the completion
of SOLVD, with 31 randomized to enalapril and 37 to
placebo. Of these, 2 enalapril and 6 placebo patients
died before the final study. In addition, 6 enalapril
patients and 1 placebo patient refused the final two
studies (before and after drug withdrawal), and 1 placebo patient could not be studied for a technical reason
(inability to gate). Study drug had been discontinued
before study end in 2 enalapril patients (1 because of
adverse effect and 1 with institution of open-label ACE
inhibitor because of clinical deterioration) and in 4
placebo patients (all with institution of open-label ACE
inhibitor because of clinical deterioration). Thus, 46
patients -21 enalapril and 25 placebo patients - had
data available through completion of SOLVD, before
and after withdrawal of study drug.
Table 1 lists baseline clinical characteristics of the
populations enrolled in the radionuclide and catheterization studies, comparing findings between the enalapril and placebo groups. Table 2 lists the same information for those patients who underwent at least baseline
and 1-year studies. There were no significant differences
between enalapril and placebo groups for any baseline
characteristics.
Heart rate, blood pressure, and radionuclide-derived
parameters, measured before randomization and at the
various time points after randomization to either placebo or enalapril, are listed in Table 3. There was no
difference between enalapril and placebo groups with
regard to any parameter at baseline. Systolic blood
pressure was reduced at 1 year compared with baseline
in enalapril-treated patients. However, blood pressure
2280
Circulation Vol 88, No 5, Part 1 November 1993
TABLE 2. Baseline Characteristics for Patients
Undergoing Study Before Randomization and at 1 Year
Radionucilde
Catheterization
Study (n=86)
Study (n=29)
Enalapril Placebo Enalapril Placebo
(n=42) (n=44) (n=19) (n=10)
54
58
58
58
90
93
95
70
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Mean age, y
Men, %
Etiology, %
84
84
90
88
Coronary disease
12
16
16
10
Dilated cardiomyopathy
Medications, %
14
11
0
0
Digoxin
7
0
0
9
Diuretics
42
33
30
40
Vasodilators
(non-ACE inhibitors)
EF, % (mean±SD)
28+6
29±7 30+5 30+5
ACE indicates angiotensin converting enzyme and EF, ejection fraction.
trended downward in placebo-treated patients as well,
and the difference between the two groups was not
statistically significant. Heart rate was not significantly
changed in either group.
Over the entire study period, LV end-diastolic and
end-systolic volumes trended upward in the placebo
group and downward in the enalapril group. Repeatedmeasures analysis applied to all time points indicated a
significant difference (P<.05) between enalapril and
placebo groups in change from baseline in end-diastolic
volume. Differences between the two groups by analysis
of covariance were not statistically significant at 1 year.
However, at the end of the study (an average of 25
months after randomization), the difference between
the enalapril and placebo groups was significant in
terms of change from baseline in end-diastolic volume
(P=.02) and was of marginal significance in terms of
change in end-systolic volume (P= .055). In the enalapril
group, LV ejection fraction increased from baseline
slightly but significantly (P<.002) at 1 year, although
this change did not represent a significant difference
from the placebo group. There were no significant
differences between the two patient groups with regard
to change in LV stroke volume or LV minute output.
There was no significant difference in enalapril effect on
LV volumes for patients receiving digoxin, diuretics, or
non-ACE inhibitor vasodilators at baseline compared
with those who were not receiving these drugs.
Fig 1 depicts the average LV pressure-volume loops
for 29 patients (19 enalapril, 10 placebo) undergoing
catheterization at baseline and at 1 year. The entire
curve was shifted slightly rightward in the placebo group
and leftward in the enalapril group. Within this group of
patients in whom baseline LV volumes were somewhat
larger than within the overall radionuclide study group,
the 1-year changes in both end-diastolic and end-systolic
volumes were significantly different for the enalapril
group vs the placebo group (both P<.01). There were
no significant changes from baseline and no significant
differences between the two groups in LV end-diastolic,
end-systolic, or peak-systolic pressures.
After withdrawal of study drug, LV volumes trended
upward in the enalapril group but did not reach the
higher levels observed in the placebo group. Repeatedmeasures analyses were applied to volumetric data in
two ways: (1) restricting the analysis to all data points
before drug withdrawal and (2) including the withdrawal data point. By both analyses, differences between the two groups were significant in terms of
end-diastolic volume (P=.03 before drug withdrawal
and P=.03 including withdrawal data). However, after
withdrawal, treatment differences in LV volumes between enalapril and placebo groups were no longer
significant based on analysis of covariance. There were
no adverse clinical events observed after withdrawal of
study drug.
Measurements of plasma renin activity indicated that
ACE inhibitor effect had been lost after withdrawal of
enalapril. In the enalapril group, plasma renin activity
increased from 0.6+0.4 ng. mL-. h` at baseline to
6.9+7.7 ng * mL- * h` (P<.005) just before drug withdrawal. This value decreased to 1.0±0.8 ng * mL-'* h(P<.005) at the time of the postwithdrawal radionuclide
study. In placebo patients, plasma renin activity did not
change significantly during the study period (1.0+0.8,
1.3±0.9, 1.7±+1.4 ng * mL-' h-' at the same three time
points, respectively).
Fig 2 compares changes in LV volumes throughout
the entire study period in the two patient groups with
those previously reported in patients with symptomatic
heart failure (SOLVD treatment trial). The average
duration of follow-up was greater in the treatment trial
because patient recruitment was more rapid than in the
prevention trial. At 1 year, the treatment difference
between enalapril and placebo groups was significantly
greater for symptomatic than for asymptomatic patients
in terms of both end-diastolic (P<.02) and end-systolic
(P<.02) volumes. At end of study, P values for comparison of treatment differences (asymptomatic vs symptomatic patients) were .06 and .04 for end-diastolic and
end-systolic volumes, respectively. These differences
resulted from both greater increases in volumes in the
placebo group and greater decreases in the enalapril
group for symptomatic patients compared with asymptomatic patients.
Discussion
We previously reported results of serial ventricular
volumetric and hemodynamic measurements from patients enrolled in the SOLVD treatment trial.2 These
findings indicated that the left ventricle progressively
dilates in patients with symptomatic LV systolic dysfunction because of dilated cardiomyopathy or remote
myocardial infarction, and this progression is prevented
by administration of an ACE inhibitor. The present
investigation examined patients enrolled in the SOLVD
prevention trial, a study designed to determine the
effects of ACE inhibitor treatment among patients with
LV systolic dysfunction, but without overt heart failure.
Within the overall prevention trial, the difference in
all-cause mortality was not statistically significant, but
enalapril significantly reduced the frequency of development of symptomatic heart failure and of heart
failure-related hospitalizations. 4
Konstam et al Enalapril Effect on Ventricular Dilatation
TABLE 3. Results: Heart Rate, Blood Pressure, and Radionuclide Measurements
1 Year
Baseline
Baseline'
25 mo2
(n=86)
(Placebo=44, Enalapril=42)
(n=46)
(Placebo=25, Enalapril=21)
HR, min-1
Placebo
69±14
67+11
68±15
66±11
Enalapril
2281
Withdrawal
73±11
71±12
71±10
68±8
68±13
69±9
128±18
130±15
123±13
124±15*
123±16
130±15
125±17
124±14
123±17
128±14
77±9
80±9
76±8
77±9
75±9
77±9
77±8
75±8
75±9
77±6
129±39
125±30
133±41
124±30
119±28
120±25
124±33
113±25*
124±33
115±25§
93±35
91±26
94±39
87±26
84±25
83±20
86±28
78±20
88±29
80±21
29±7
28±6
30±8
31 ±5t
30±6
31±4
31±8
32±5
30±7
31±5
Systolic BP,
mm Hg
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Placebo
Enalapril
Diastolic BP,
mm Hg
Placebo
Enalapril
LVEDVI, mL/m2
Placebo
Enalapril
LVESV, mL/m2
Placebo
Enalapril
LVEF, %
Placebo
Enalapril
LVSV, mL/m2
Placebo
36±10
38±11
35±10
38±12
36±11
Enalapril
34±9
37±8t
36±7
35±8
35±7
LVCO,
L min-1 . m-2
Placebo
2.4±0.6
2.5±0.6
2.3±0.5
2.4±0.4
2.3±0.5
Enalapril
2.5±0.7
2.6±0.6
2.6±0.5
2.4±0.4
2.4±0.4
HR indicates heart rate; BP, blood pressure; CO, cardiac output; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic
volume; LV, left ventricular; and SV, stroke volume.
Data are mean±SD. 'Baseline values for patients enrolled at the two centers performing scans at an average of 25 months and after
withdrawal. 2Average follow-up (range, 13 to 45 months) on study drug.
*P<.05, tP<.01 vs baseline; tP<.05 enalapril vs placebo treatment effect by analysis of covariance; §P<.05 vs prior (prewithdrawal)
measurement; IIP<.05 enalapril vs placebo treatment effect by repeated-measures analysis applied to all time points.
Our findings indicate that among asymptomatic patients, the progression of ventricular dilatation and
systolic dysfunction is slower than what we previously
observed within symptomatic patients. Partly for this
reason, differences between enalapril- and placebotreated patients are smaller. Nevertheless, at an average
of 25 months, enalapril had prevented the left ventricular dilatation observed within the placebo group. It
seems likely that asymptomatic and symptomatic patients represent a continuum of pathology, the progression of which accelerates at later stages. ACE inhibitors
appear to exert a beneficial influence at any stage, but
this benefit is more evident in the presence of more
advanced disease.
Numerous prior studies in animal models and in
humans have demonstrated LV myocardial hypertrophy
and remodeling in the days and weeks after myocardial
infarction.'3-18 These changes resulting in progressive
ventricular dilatation appear to continue for years after
the initial myocardial insult. Although the exact stimuli
effecting these changes in myocardial structure remain
unknown, increased myocardial wall stress has been
postulated to represent an initiating factor. Activation
of the renin-angiotensin system appears to play an
important role in the pathogenesis of ventricular remodeling'9-21 by contributing to the increase in wall stress
and possibly by direct myocardial effects.
The SOLVD population, identified on the basis of
reduced LV ejection fraction, was divided into treatment and prevention cohorts solely on the basis of
clinical findings. In contrast to treatment trial patients,
patients randomized into the prevention trial had no
overt manifestations of heart failure and were therefore
not thought by their physicians to require treatment for
heart failure. As further evidence that their disease was
less severe or less advanced at baseline, prevention trial
patients had a higher mean ejection fraction2'4'22 and
lower mean LV end-diastolic and end-systolic volumes.2
In addition, they had significantly less activation of the
renin-angiotensin system.3 The median plasma renin
2282
Circulation Vol 88, No 5, Part 1 November 1993
or both of these classes of agents accelerates the progression of LV dilatation. Additional investigation may
be warranted to explore this possibility.
ACE inhibitors have been found to slow or halt the
progression of ventricular remodeling and dilatation in
animal models and in humans.1'2'19'20'2324 This effect is
likely to be partly or solely responsible for the observed
reduction in mortality among patients with symptomatic
LV systolic dysfunction22 and among patients with recent myocardial infarction and reduced ejection fraction.25 The effect of ACE inhibitors on LV dilatation
does not appear to be limited to patients in whom
therapy is initiated soon after myocardial infarction.
Among patients with myocardial infarction, entry into
either of the SOLVD trials was delayed until at least 30
days after the event. Our present findings extend the
observed inhibition of ventricular remodeling by ACE
inhibitors to patients without overt heart failure.
The difference in ventricular volumetric changes between placebo- and enalapril-treated patients partly
results from an ongoing effect by the ACE inhibitor on
ventricular systolic and diastolic load. After withdrawal
of enalapril, ACE inhibitor effect was lost, as evidenced
by a return in plasma renin activity to the level observed
in the placebo group. LV volumes returned toward
baseline but did not reach the higher levels observed
within placebo patients. Thus, it appears likely that net
effects represent a combination of ongoing alteration in
load and prevention of remodeling.
The distinction between patients with asymptomatic
and symptomatic ventricular systolic dysfunction is not
absolute. Rather, it is likely that a continuous progression exists with regard to ventricular dysfunction, neurohormonal activation, and clinical manifestations of
heart failure. The progression of these physiological and
functional derangements may be nonlinear. After recovery from an initial myocardial insult but while LV
dysfunction remains subclinical, the rate of ventricular
ENALAPRIL
PLACEBO
z
E
E
'U
W
m.
90.110.130.150
0
0
9
150
170
70
90
110
90
130
1 30
110
n15 9
1 50
17,0
VOLUME (ml/m2)
VOLUME (mUm2)
FIG 1. Mean left ventricular pressure-volume loops at
baseline and 1 year in patients randomized to placebo
and to enalapril. At 1 year, the entire curve was shifted to
the right for the placebo group and to the left for the
enalapril group.
Downloaded from http://circ.ahajournals.org/ by guest on June 12, 2017
level within prevention trial patients was only slightly
higher than in a normal control group.3 Thus, our
finding that ventricular dilatation progressed more
slowly in prevention trial patients is consistent with the
concept that the rate of ventricular remodeling is related to the severity of baseline LV dysfunction, to the
magnitude of diastolic wall stress, and to the degree of
activation of the renin-angiotensin system. It seems
likely that the lesser baseline ventricular dysfunction
and the slower progression of ventricular dilatation in
prevention trial patients relate directly to the substantially lower mortality rates observed in the prevention
trial as compared with the treatment trial.4'22
By design, patients within the two SOLVD trials
differed with regard to background therapy. A far larger
proportion of treatment trial patients compared with
prevention trial patients were receiving digitalis and/or
diuretics, and we cannot exclude the possibility that one
END-DIASTOLIC VOLUME
TREATMENT
PREVENTION
165-
165'
145mil/M2
145
.
PLACEBO
wd
~(IT~9.034
0
,
12
p=0.03
wd
MONTHS
125
ENALAPRIL
wd
EHAPRIL
A
wd
n=11
125.
105 g
PLACEBO
,
24
1
inn
l a;}
I
0
12
24
MONTHS
36
FIG 2. Left ventricular (LV) end-diastolic volumes (mean±SE) in enalapril and placebo patients within the prevention trial and the previously reported treatment trial who had
measurements made at all five time points. Measurements are at baseline, 4 months, 1 year, and
at study end (mean of 25 months and 33 months
for prevention trial and treatment trial patients,
respectively). The final data point on each graph
is after withdrawal (wd) of study drug for a minimum of 5 days. P values shown are for comparison of placebo and enalapril groups by repeated-measures analysis applied to all time points.
Baseline volumes were significantly higher in
treatment trial patients (P<.005). In the prevention trial and the treatment trial, placebo-treated
patients manifested progressive increases in
ventricular volumes, whereas enalapril-treated
patients showed an early and sustained reduction in LV volumes. Treatment difference between placebo and enalapril groups was significantly greater within the treatment trial than within
the prevention trial (P<.02 at 1 year).
Konstam et al Enalapril Effect on Ventricular Dilatation
dilatation and remodeling is slow, and discernible benefits of ACE inhibition are relatively slight. Nevertheless, these effects on ventricular dilatation appear to be
important and coincide with a demonstrable reduction
in the rate of transition to overt heart failure.4 In
patients with more advanced ventricular dilatation and
symptoms of heart failure, progressive ventricular dilatation appears to be more rapid, and clinical events,
including deaths, are more common. In this population,
ACE inhibitor effects on ventricular remodeling and on
mortality are more evident. Thus, during the early
stages of ventricular dilatation, therapeutic efforts
should be directed toward preventing the transition to a
stage of accelerated progression of structural and functional derangement.
Acknowledgments
This study was supported by National Heart, Lung, and
Blood Institute contract N01-HC55010, National Institutes of
Health, Bethesda, Md.
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Circulation. 1993;88:2277-2283
doi: 10.1161/01.CIR.88.5.2277
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