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Journal of the American College of Cardiology
© 2004 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 43, No. 12, 2004
ISSN 0735-1097/04/$30.00
doi:10.1016/j.jacc.2003.10.073
Left Ventricular Mass in Cardiac Disease
Effects of Ramipril on Left Ventricular
Mass and Function in Cardiovascular
Patients With Controlled Blood Pressure and
With Preserved Left Ventricular Ejection Fraction
A Substudy of the Heart Outcomes Prevention Evaluation (HOPE) Trial
Eva Lonn, MD, MSC, FACC, FRCPC,*† Roya Shaikholeslami, MD,*† Qilong Yi, PHD,†‡
Jackie Bosch, MSC,† Brian Sullivan, MD, FRCPC,* Paul Tanser, MD, FACC, FRCPC,*
Alison Magi, RN,† Salim Yusuf, MBBS, DPHIL, FACC, FRCPC*†
Hamilton and Toronto, Ontario, Canada
The purpose of this study was to assess the effects of ramipril on left ventricular mass (LVM)
and function in vascular disease patients with controlled blood pressure (BP) and with
preserved left ventricular ejection fraction (LVEF).
BACKGROUND Increased LVM and left ventricular (LV) volume and decreased LVEF predict clinical events.
Angiotensin-converting enzyme inhibitors reduce LVM and LV volume and preserve LVEF
in patients with hypertension and/or LV dysfunction, but have not been studied in patients
with controlled BP and preserved LVEF.
METHODS
We compared the effects of two doses of ramipril (10 mg/day and 2.5 mg/day) versus placebo
in 506 patients with vascular disease on echocardiographic measures of LVM and LV
function.
RESULTS
Baseline BP and LVEF were similar, 131/76 mm Hg and 58%, in all treatment groups. After
four years, LVM index increased by 3.98 ⫾ 2.08 g/m2 in the placebo and by 4.16 ⫾ 1.86 g/m2
in the ramipril 2.5 mg/day groups and decreased by 2.02 ⫾ 2.25 g/m2 in the ramipril 10
mg/day group (p ⫽ 0.02). The changes in LV end-diastolic and end-systolic volumes were
4.16 ⫾ 2.55 ml and 5.31 ⫾ 1.67 ml in the placebo, ⫺0.43 ⫾ 2.75 ml and 2.90 ⫾ 1.45 ml
in the ramipril 2.5 mg/day, and ⫺5.90 ⫾ 2.93 ml and ⫺1.90 ⫾ 1.55 ml in the ramipril 10
mg/day groups (p ⫽ 0.02 and p ⫽ 0.001). The changes in LVEF were ⫺2.02 ⫾ 0.72%,
⫺1.54 ⫾ 0.74%, and ⫺0.17 ⫾ 0.72%, respectively (p ⫽ 0.01).
CONCLUSIONS Ramipril has beneficial effects on LV structure and function in vascular patients with
controlled BP and with preserved LVEF. (J Am Coll Cardiol 2004;43:2200 – 6) © 2004 by
the American College of Cardiology Foundation
OBJECTIVES
Left ventricular (LV) hypertrophy on electrocardiography or
increased left ventricular mass (LVM) on echocardiography
are strong predictors of death and nonfatal cardiovascular
events in patients with hypertension, coronary heart disease,
other cardiovascular diseases, and in the general population
(1–5). Moreover, similar to other cardiovascular risk factors,
See page 2216
such as cholesterol and blood pressure (BP), the relationship
between LVM and cardiovascular risk may extend to increases in LVM within the “normal” (average) range (5).
This may be particularly important in patients with other
markers of increased cardiovascular risk, such as those with
From the *Division of Cardiology, Department of Medicine, McMaster University,
Hamilton, Ontario, Canada; †Population Health Research Institute, McMaster
University, Hamilton, Ontario, Canada; and the ‡Princess Margaret Hospital,
Toronto, Ontario, Canada. The study was partially funded by the Medical Research
Council of Canada, grants UI-12362 and UI 12363.
Manuscript received July 14, 2003; revised manuscript received October 22, 2003,
accepted October 27, 2003.
preexisting cardiovascular disease or those with multiple risk
factors. Similarly, increased LV volume and abnormal LV
systolic function are potent predictors of events in patients
with coronary heart disease (6 – 8).
Angiotensin-converting enzyme (ACE) inhibitors reduce
LVM and regress LV hypertrophy in animal models and in
hypertensive human subjects (9 –11). Similarly, ACE inhibitors have been shown to reduce LV volumes and to improve
LV systolic function in patients with coronary heart disease
when administered early after myocardial infarction or in
those with low left ventricular ejection fraction (LVEF)
(8,12). These beneficial effects of ACE inhibitor therapy on
LVM and LV remodeling may be mediated through the
hemodynamic, BP and afterload-reducing actions of these
agents, but also through load-independent mechanisms
related to blockade of angiotensin II-mediated myocyte
hypertrophy, reduction in cardiac extracellular collagen matrix formation attained by blocking angiotensin II, and by
decrease in aldosterone release and through bradykininmediated actions (13–15).
JACC Vol. 43, No. 12, 2004
June 16, 2004:2200–6
Abbreviations and Acronyms
ACE
⫽ angiotensin-converting enzyme
ASE
⫽ American Society of Echocardiography
BP
⫽ blood pressure
HOPE
⫽ Heart Outcomes Prevention Evaluation trial
LV
⫽ left ventricle/ventricular
LVEDV ⫽ left ventricular end-diastolic volume
LVEF
⫽ left ventricular ejection fraction
LVESV ⫽ left ventricular end-systolic volume
LVM
⫽ left ventricular mass
LVMI
⫽ left ventricular mass index
NWMAB ⫽ new wall motion abnormalities
WMS
⫽ wall motion score
Patients with atherosclerotic vascular disease have increased expression of tissue renin-angiotensin systems in the
vasculature and in the heart (14,15), which could contribute
to an increase in LVM and to LV dilation. We postulated
that chronic ACE inhibitor therapy would prevent an
increase in LVM and volumes and a decline in LV systolic
function in patients with atherosclerotic vascular disease
with average (“normal”) BP and LVM and with preserved
LV systolic function. We further postulated that this effect
would be largely independent of BP-lowering. We also
sought to evaluate the relationship between ramipril dose
and its effects on LVM, volume, and function.
Therefore, we evaluated the effects of ramipril on LV
structure and function in an echocardiographic substudy of
the Heart Outcomes Prevention Evaluation (HOPE) trial
(16,17).
METHODS
Patients. Patients were recruited between December 1993
and August 1995 from three Canadian HOPE study centers, selected based on expertise and interest in the study.
The study protocol was approved by the ethics board of each
participating institution, and all patients provided informed
consent. All of the HOPE study participants from these
centers who had technically adequate baseline echocardiograms were enrolled in the echocardiographic substudy.
Over 85% of patients were recruited at McMaster University, which also served as the core echocardiography laboratory. Detailed patient eligibility criteria for the HOPE
trial have been published (16,17). In summary, patients
were eligible if they were ⱖ55 years old, had vascular disease
or diabetes and at least one additional cardiovascular risk
factor and did not have heart failure symptoms, known low
LVEF (⬍40%), uncontrolled hypertension, renal disease
(serum creatinine ⬎200 ␮mol/l or proteinuria), or other
major cardiac or noncardiac illness. To be eligible for the
echocardiographic substudy, patients had to have also an
adequate baseline echocardiographic examination, defined
as availability of recordings of good or fair quality for
M-mode and two-dimensional echocardiography, allowing
Lonn et al.
Ramipril Improves LV Structure and Function
2201
measurements of at least two of the echocardiographic
outcome measurements of LVM, LV volumes, and LVEF.
Study design, randomization, interventions, and followup. The echocardiographic substudy of the HOPE trial
was a randomized, double-blind, placebo-controlled trial
that evaluated two doses of ramipril (2.5 mg/day and 10
mg/day). Patients were also randomized to 400 IU/day of
vitamin E or placebo, as part of the parent HOPE trial. The
study was designed to have ⬎80% power to detect a change
of 10 g/m2 in left ventricular mass index (LVMI) assuming
a standard deviation of 25 g/m2. Baseline echocardiograms
were performed at the randomization visit. Follow-up visits
occurred one month after randomization and every six
months thereafter. Study-end echocardiograms were performed at the four-year visit. Blood pressure was measured
by experienced study nurses at randomization, one month,
two years, and study end using standard sphygmomanometers and a standardized protocol (study visits generally
occurred during morning hours, use of appropriate cuff size
was ensured, patients were left alone supine for ⱖ5 min,
thereafter two exact readings avoiding rounding were obtained from each arm, and the lowest readings from the left
and right arms were averaged). The study protocol did not
include algorithms for the management of cardiovascular
risk factors, and the study drug dose was not titrated to
attain predefined BP goals. The patients’ usual (clinical)
physician(s) managed all cardiovascular risk factors, including BP. The study protocol and the study personnel strongly
recommended adherence to contemporary guidelines for the
management of cardiovascular risk factors. The open-label
use of ACE inhibitors for BP management alone was not
allowed. These agents could be used only when clear new
changes in the patients’ clinical status occurred, for which
ACE inhibitor therapy is generally strongly recommended.
If such clinical changes were transient, every effort was made
to discontinue treatment with open-label ACE inhibitors.
Echocardiographic methods. Echocardiograms were acquired by trained study sonographers following a standardized protocol and using high-quality commercially available
echocardiographs equipped with 3.0- to 3.5-MHz and 2.0to 2.5-MHz probes. Standardized examinations included
two-dimensional-guided M-mode recordings obtained in
the parasternal long- and short-axis views below the mitral
leaflet tips to the nearest millimeter and two-dimensional
parasternal long- and short-axis (at the mitral leaflets,
midpapillary, and apical levels) and apical (four-chamber,
two-chamber, and long-axis) views. All measurements were
performed off-line by one reader (R.S.) blinded to subjects’
randomization status and clinical data and using a computerized review station (Freeland Systems, Cine View, Indianapolis, Indiana). A minimum of three cardiac cycles for
patients in sinus rhythm and five cardiac cycles for patients
in atrial fibrillation were captured and measured. The
M-mode measurements included end-diastolic LV internal
diameter, interventricular septal thickness and posterior wall
thickness, and end-systolic and LV internal diameter. Cases
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Ramipril Improves LV Structure and Function
where accurate M-mode measurements could not be obtained in the parasternal short axis were substituted by
parasternal long-axis measurements. All M-mode measurements were performed using the American Society of
Echocardiography (ASE) leading-edge convention (18).
When optimal orientation of the LV imaging views could
not be obtained, correctly oriented two-dimensional linear
measurements were obtained using the ASE leading-edge
convention. The LVM was calculated using the corrected
ASE method (19), and LVMI was obtained by indexing for
body surface area. Between-sonographer (on 83 duplicate
examinations) and within-reader (on 80 duplicate readings)
intraclass correlation coefficients for LVM were 0.84 and
0.85, respectively. Two-dimensional LVM, left ventricular
end-diastolic volume (LVEDV) and left ventricular endsystolic volume (LVESV), and LVEF were calculated from
two-dimensional recordings using the modified biplane
Simpson’s method (20). Wall motion score (WMS) and
new wall motion abnormalities (NWMAB) were evaluated
on two-dimensional echocardiograms using the 16-segment
model (21). Between-sonographer and within-reader (on 20
duplicate readings) intraclass correlation coefficients for
LVEF measurements were 0.70 and 0.75, respectively.
Reproducibility of two-dimensional LVM measurements
was lower than that of M-mode measurements and, therefore, the latter were used for the primary analysis of
treatment effects on LVM and LVMI. An attempt was
made to obtain all measurements from all echocardiograms
of all 446 patients included in the final analysis. However, at
times the image quality was suboptimal. Consequently, not
all measurements were obtained in every patient. M-mode
LVM calculations were possible in 99% of the patients;
two-dimensional measurements of LVEDV, LVESV,
LVEF, LVM, and WMS were obtained in 98%, 98%, 98%,
96%, and 98% of patients, respectively.
Predefined echocardiographic outcome measurements
were the changes between study end and baseline in LVM,
LVMI, LVEDV, LVESV, LVEF, and WMS. In addition,
the effect of the study intervention on NWMAB was
evaluated.
Statistical analysis. All analyses were by intention-to-treat
and were done in SAS 8.0 (SAS Institute, Cary, North
Carolina). Baseline characteristics were compared by oneway analysis of variance and chi-square tests as appropriate.
There was no significant interaction between ramipril and
vitamin E for any of the echocardiographic measurements.
Therefore, analyses were done to evaluate the overall impact
of ramipril on each predefined echocardiographic outcome
and to compare differences between each of the two doses of
ramipril versus placebo. The predefined primary analysis
was by analysis of variance, with changes in LVM, LVMI,
LVEDV, LVESV, WMS, and NWMAB, respectively, as
the dependent variables and treatment assignment and
baseline measurements of the echocardiographic parameter
analyzed as the independent variables. In addition, analyses
controlling for age, gender, and baseline echocardiographic
JACC Vol. 43, No. 12, 2004
June 16, 2004:2200–6
measurements, for changes in systolic and in diastolic BP
and with multivariate adjustment for baseline imbalances,
and for other variables that may influence LVM and
function (age, gender, body mass index, history of hypertension, and history of coronary heart disease) were performed by analysis of covariance. The analysis evaluating the
overall ramipril effect used ramipril as a continuous variable
with values of 0, 2.5 mg, and 10 mg in the model to test the
linear impact of ramipril on LVM and function. Dunnett’s
test for comparison of multiple treatments against one
control was applied in the analyses comparing each dose of
ramipril versus placebo. For all analyses, the level of statistical significance was set at p ⬍ 0.05.
RESULTS
Baseline characteristics, follow-up, and compliance. A
total of 506 patients were enrolled in the study. The baseline
characteristics were well-balanced with the exception of
small differences in body mass index and in history of
coronary heart disease (Table 1). A total of 446 patients
completed the study, 151 in the placebo, 149 in the ramipril
2.5 mg/day, and 146 in the ramipril 10 mg/day groups.
Their baseline characteristics were similar to those of the
506 patients randomized and were also well-balanced.
Clinical follow-up was complete in all study patients. Of
the initial 506 study patients, 44 (9%) died, and 16 (3%)
missed the study-end echocardiogram due to illness or
change in residence or had inadequate study-end echocardiograms. Thus, study-end echocardiograms were obtained
in 446 study participants (88% of all randomized patients
and 97% of those alive at study end). Adherence and use of
non-study ACE inhibitors are shown in Table 2.
BP changes. Both systolic and diastolic BP was wellcontrolled at baseline, 131/76 mm Hg, and similar in the
three treatment arms. Mean baseline, one month, two years,
and study-end BP measurements are shown in Table 3.
Effects of ramipril on LVM and function. Ramipril
significantly reduced the change in LVM (p ⫽ 0.03 for the
overall dose-dependent effect of ramipril in the analysis of
variance analysis) and LVMI (p ⫽ 0.02 for the overall effect
of ramipril). The benefit of ramipril therapy on LVM and
LVMI remained statistically significant after adjustment for
age, gender, and baseline LVM and LVMI, respectively,
and after adjustment for changes in systolic and in diastolic
BP (p ⬍ 0.05). In the multivariate model adjusting for
baseline imbalances and predictors of LVM and function,
similar trends were observed (p ⫽ 0.08 for the change in
LVM and in LVMI). The treatment benefit was derived
entirely from the ramipril 10 mg/day group with no significant changes for the comparison between the ramipril 2.5
mg/day versus placebo groups (Table 4). The mean differences in the changes in LVM and in LVMI between the
ramipril 10 mg/day and placebo groups were 11.74 g and
6.0 g/m2, respectively. The change in the sum of the
interventricular septal thickness and posterior wall thick-
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Ramipril Improves LV Structure and Function
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June 16, 2004:2200–6
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Table 1. Baseline Clinical and Echocardiographic Characteristics
Age
% Female
History of (%)
Coronary heart disease*
Prior MI
Prior CABG
Hypertension
Diabetes
Dyslipidemia (high total cholesterol or
low HDL cholesterol)
Current smoking
Stroke
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Resting HR (beats/min)
BMI (kg/m2)*
Drug use (%)
Aspirin
Beta-blocker
Diuretics
Calcium channel blocker
Lipid lowering
Baseline echocardiographic measurements
M-mode
IVST (mm)
PWT (mm)
LVIDd (mm)
LVM (g)
LVMI (g/m2)
LA (mm)
Two-dimensional
LVM (g)
LVMI (g/m2)
LVEDV (ml)
LVESV (ml)
LVEF (%)
WMS
Placebo
n ⴝ 168
Ramipril 2.5 mg/day
n ⴝ 171
Ramipril 10 mg/day
n ⴝ 167
65.5 ⫾ 6.8
19.6
65.3 ⫾ 6.6
24.6
65.3 ⫾ 6.3
25.8
85.7
59.5
32.7
31.6
36.3
54.2
88.3
61.4
33.9
31.6
31.0
51.5
78.4
56.3
26.4
40.7
37.1
52.1
9.6
6.0
131.0 ⫾ 17.9
75.3 ⫾ 8.3
66.2 ⫾ 10.8
28.5 ⫾ 4.8
9.9
5.3
130.2 ⫾ 17.2
76.5 ⫾ 9.9
66.5 ⫾ 10.9
27.1 ⫾ 3.6
10.8
5.4
131.4 ⫾ 15.2
75.9 ⫾ 9.6
66.6 ⫾ 10.9
28.1 ⫾ 4.5
85.1
44.1
9.5
19.1
35.7
84.8
41.5
11.7
11.1
38.6
77.8
43.7
12.0
16.8
27.0
9.93 ⫾ 2.01
9.30 ⫾ 1.63
53.86 ⫾ 6.33
198.45 ⫾ 54.23
101.89 ⫾ 24.43
40.41 ⫾ 5.61
9.89 ⫾ 1.85
9.03 ⫾ 1.50
53.40 ⫾ 6.31
190.30 ⫾ 51.07
101.02 ⫾ 24.15
39.47 ⫾ 4.92
10.15 ⫾ 2.01
9.23 ⫾ 1.49
53.73 ⫾ 6.84
199.48 ⫾ 59.13
103.42 ⫾ 27.57
40.20 ⫾ 5.20
174.09 ⫾ 48.97
89.27 ⫾ 21.58
109.78 ⫾ 31.01
47.10 ⫾ 18.80
57.86 ⫾ 9.44
1.20 ⫾ 0.26
172.54 ⫾ 50.07
91.81 ⫾ 24.56
108.38 ⫾ 36.66
46.59 ⫾ 22.81
58.38 ⫾ 8.83
1.23 ⫾ 0.30
179.31 ⫾ 56.84
93.73 ⫾ 24.82
110.04 ⫾ 44.66
49.77 ⫾ 26.07
58.21 ⫾ 9.58
1.17 ⫾ 0.24
*p ⬍ 0.05; †Only 14 patients (2.8%) had left ventricular ejection fraction (LVEF) ⬍ 40% at baseline.
BMI ⫽ body mass index; BP ⫽ blood pressure; CABG ⫽ coronary artery bypass graft surgery; HDL ⫽ high-density lipoprotein; HR ⫽ heart rate; IVST ⫽ interventricular
septal thickness in end-diastole; LA ⫽ left atrial side; LVEDV ⫽ left ventricular end-diastolic volume; LVESV ⫽ left ventricular end-systolic volume; LVIDd ⫽ left ventricular
internal diameter in end-diastole; LVM ⫽ left ventricular mass; LVMI ⫽ left ventricular mass index; MI ⫽ myocardial infarction; PWT ⫽ posterior wall thickness in
end-diastole; WMS ⫽ left ventricular wall motion score.
ness, which reflects the thickness of the myocardium and is
largely load-independent, was reduced by treatment with
ramipril 10 mg/day (mean difference, 0.57 mm; p ⬍ 0.05).
The main analyses of the treatment effect on changes in
Table 2. Compliance (%)
Year
Placebo
Ramipril 2.5 mg/day
Ramipril 10 mg/day
1
2
3
Study end
94.0
89.0
89.5
87.5
88.6
83.0
81.5
83.1
84.2
81.6
82.1
79.2
Values are percentages of patients taking ⬎75% of study medications. Clinical
progression of disease may have resulted in the need for open-label angiotensinconverting enzyme (ACE) inhibitors. Open-label ACE inhibitor use at any time
during the study (including transient use) was 19.97% in the placebo, 14.8% in the
ramipril 2.5 mg/day, and 13.0% in the ramipril 10 mg/day groups. The most common
causes for open-label ACE inhibitor use were the development of heart failure (25.0%
of all open-label ACE inhibitor use), new left ventricular dysfunction (19.1%), new or
worsening proteinuria (17.6%), and suboptimal blood pressure control after attempts
to control blood pressure without the use of ACE inhibitors (22.0%).
LVM and LVMI were derived from M-mode echocardiography. Data obtained from two-dimensional echocardiography also showed similar significant treatment benefits
for ramipril. The mean differences in two-dimensional
echocardiographic measurements of changes in LVM and in
LVMI between the ramipril 10 mg/day and placebo groups
were 14.06 g (p ⫽ 0.03) and 7.21 g/m2 (p ⫽ 0.03),
respectively.
The LVEDV and LVESV increased over time in the
placebo arm of the trial, but decreased in the ramipril 10
mg/day group, with similar but statistically not significant
trends for the ramipril 2.5 mg/day group (Table 4). The
overall treatment effect of ramipril and the effect of ramipril
10 mg/day on changes in LVEDV and in LVESV remained
statistically significant after adjusting for age, gender, and
baseline LVEDV and LVESV, respectively, for changes in
systolic and in diastolic BP and in the multivariate model.
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Ramipril Improves LV Structure and Function
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June 16, 2004:2200–6
Table 3. Systolic and Diastolic Blood Pressure at Baseline and in Follow-Up
Systolic BP, mm Hg
Placebo
Ramipril 2.5 mg/day
Ramipril 10 mg/day
Diastolic BP, mm Hg
Placebo
Ramipril 2.5 mg/day
Ramipril 10 mg/day
Baseline
1 Month
2 Years
Study End
131.0 ⫾ 17.9
130.3 ⫾ 16.7
131.3 ⫾ 15.1
128.1 ⫾ 17.9†
123.5 ⫾ 16.7§
126.4 ⫾ 15.4§
129.8 ⫾ 16.1
123.6 ⫾ 15.5§
125.9 ⫾ 17.3‡
134.2 ⫾ 18.3†
130.6 ⫾ 16.6
132.5 ⫾ 17.3
75.3 ⫾ 8.3
76.5 ⫾ 9.9
75.9 ⫾ 9.6
75.9 ⫾ 9.5
74.0 ⫾ 9.7‡
74.6 ⫾ 8.9*
74.0 ⫾ 9.9
71.5 ⫾ 9.1§
71.7 ⫾ 8.9§
72.5 ⫾ 8.9†
72.0 ⫾ 8.5§
72.6 ⫾ 9.4‡
Values are mean ⫾ SD. *p ⬍ 0.05, †p ⬍ 0.01, ‡p ⬍ 0.001, and §p ⬍ 0.0001 for comparisons versus baseline blood pressure
(BP). Compared with the placebo group, the systolic and diastolic BP changes versus baseline were significantly higher at one
month and two years but not at study end in the ramipril 2.5 mg/day and 10 mg/day groups. The blood pressure changes did
not differ significantly between the ramipril 2.5 mg/day and 10 mg/day groups.
The differences in LVEDV and LVESV between the
ramipril 10 mg/day and the placebo groups were 10.06 ml
(p ⫽ 0.019) and 7.21 ml (p ⫽ 0.002), respectively.
Baseline LVEF was well-preserved and similar, 58%, in
all three study groups. In patients assigned to the placebo
arm of the trial, there was a 2% loss in LVEF over time,
with only minimal 0.17% loss in LVEF in the ramipril 10
mg/day group and an intermediate 1.5% loss in LVEF in
the ramipril 2.5 mg/day group (Table 3). The effect of
ramipril was statistically significant (p ⫽ 0.009 for the
overall dose-dependent ramipril effect adjusted for baseline
LVEF, p ⫽ 0.011 in the model adjusted for age, gender,
and baseline LVEF, p ⫽ 0.025 in the multivariate model,
and p ⫽ 0.062 in the model adjusted for time-dependent
changes in systolic and in diastolic BP). The mean difference between changes in LVEF in the ramipril 10 mg/day
and placebo groups was 1.85% (p ⫽ 0.018). There were
similar trends towards better WMS and fewer NWMAB in
the ramipril 10 mg/day group, although these did not reach
statistical significance (Table 4).
In order to better understand the observed treatment
benefit on LVEF, we evaluated the effects of ramipril in
patients who did and those who did not sustain a myocardial
infarction during the study. Of the 446 patients who
completed both echocardiographic examinations, 39 sustained a myocardial infarction (16 in the placebo, 12 in the
ramipril 2.5 mg/day, and 11 in the ramipril 10 mg/day
groups), and their LVEF changes did not differ significantly, probably due to the small number of observations
and the limited power of this analysis. Among the 407
patients who did not sustain a myocardial infarction during
the study, there was a significant treatment effect (p ⫽ 0.028
for the overall dose-dependent ramipril effect and p ⫽ 0.019
for the comparison between the ramipril 10 mg/day and the
placebo groups). These differences remained statistically
significant in the model adjusted for age, gender, and
baseline LVEF and in the multivariate model, with a strong
trend (p ⫽ 0.06) in the analysis corrected for systolic and for
diastolic BP changes.
Clinical outcomes. As expected in this relatively small
substudy, there were no statistically significant differences in
the primary clinical outcome (the composite of cardiovascular death, myocardial infarction, and stroke) that occurred
in 32 patients (19.1%) in the placebo, 24 (14%) in the
ramipril 2.5 mg/day, and 25 (15%) in the ramipril 10
mg/day groups. Reliable data on clinical outcomes are
provided by the adequately powered parent HOPE trial
(17).
DISCUSSION
We demonstrated that long-term therapy with the ACE
inhibitor ramipril has favorable effects on LV structure and
function, by reducing LVM, LV volumes, and the loss in
Table 4. Effects of Ramipril on Left Ventricular Mass and Function
Placebo
n ⴝ 151
⌬LVM (g)
⌬LVMI (g/m2)
⌬LVEDV (ml)
⌬LVESV (ml)
⌬LVEF (%)
⌬WMS
NWMAB
8.21 ⫾ 4.01
3.98 ⫾ 2.08
4.16 ⫾ 2.55
5.31 ⫾ 1.67
⫺2.02 ⫾ 0.72
0.05 ⫾ 0.01
31 (20.8%)
Ramipril 2.5 mg/day
n ⴝ 149
Ramipril 10 mg/day
n ⴝ 146
p for Trend*
7.86 ⫾ 3.54
4.16 ⫾ 1.86
⫺0.43 ⫾ 2.75
2.90 ⫾ 1.45
⫺1.54 ⫾ 0.74
0.029 ⫾ 0.01
30 (20.4%)
⫺3.53 ⫾ 4.40†
⫺2.02 ⫾ 2.25†
⫺5.90 ⫾ 2.93†
⫺1.90 ⫾ 1.55‡
⫺0.17 ⫾ 0.72†
0.018 ⫾ 0.01§
23 (15.8%)
0.03
0.02
0.02
0.001
0.01
0.06
0.24
Values are means ⫾ SEM; all changes (⌬) in echocardiographic measurements are calculated as study end minus baseline values.
*Corrected for baseline value; †p ⬍ 0.05 for the comparison of ramipril 10 gm/day versus placebo; ‡p ⬍ 0.01 for the comparison
of ramipril 10 mg/day versus placebo; §p ⫽ 0.06 for the comparison of ramipril 10 mg/day versus placebo.
⌬LVEDV ⫽ change in left ventricular end-diastolic volume measured by two-dimensional echocardiography; ⌬LVEF ⫽
change in left ventricular ejection fraction measured by two-dimensional echocardiography; ⌬LVESV ⫽ change in left
ventricular end-systolic volume measured by two-dimensional echocardiography; ⌬LVM ⫽ change in left ventricular mass
measured by M-mode echocardiography; ⌬LVMI ⫽ change in left ventricular mass index measured by M-mode echocardiography; ⌬WMS ⫽ change in wall motion score; NWMAB ⫽ new wall motion abnormalities.
JACC Vol. 43, No. 12, 2004
June 16, 2004:2200–6
LVEF in high-risk patients with vascular disease, with
well-controlled BP, and with average (“normal”) baseline
LVM, LV volume, and LVEF. These are novel observations, as previous clinical ACE inhibitor studies have
selected patients based on elevated BP and/or increased
LVM or depressed LV systolic function. Furthermore, in
such previous trials, ACE inhibitor dose was generally
titrated based on BP response.
Both ramipril 10 mg/day and 2.5 mg/day had significant,
but modest, BP-lowering effects at one month and at two
years after randomization although, by study end, systolic
BP returned to baseline levels in the active treatment groups
and increased in the placebo group. The magnitude of
BP-lowering was similar for the two ramipril doses, which
may be related to the fact that most study patients were
taking various other anti-ischemic drugs at different doses,
not controlled by the study protocol. By contrast, the
benefits of ramipril on LVM, LV volumes, and LV function
were observed with the higher dose of 10 mg/day, while the
lower dose of 2.5 mg/day did not have a significant impact.
These observations suggest that the benefits of ACE inhibitor therapy on LVM and function are, at least in part,
independent of BP-lowering. Furthermore, statistical analyses adjusting for BP changes did not significantly alter the
study results for the analyses of treatment effects on LVM
and LV volumes, while for LVEF a strong trend towards
treatment benefit remained after correcting for changes in
BP (p ⫽ 0.06), and the multivariate model, which included
history of hypertension, remained statistically significant. In
the multivariate model, which adjusted for baseline LVM,
age, gender, and for baseline imbalances and other predictors of LVM, there was a strong trend for an overall ramipril
effect on LVM and LVMI (p ⫽ 0.08). While this analysis
did not reach traditional levels of statistical significance, a
strong trend was observed; this analysis is conservative and
controls not only for parameters that differed at baseline,
and, furthermore, the comparison between the ramipril 10
mg/day and the placebo groups was significant in the
multivariate model.
The beneficial effect of ramipril on LVEF was not
restricted to patients who had an interim infarct during the
study. This analysis suggests that the impact of ramipril on
preservation of LV systolic function is likely multifactorial
and cannot be explained by prevention of new infarcts or
reduction in BP alone.
Previous studies in hypertensive patients have reported
weak correlations between changes in LVM and druginduced BP reductions, and it was suggested that LVM
changes more closely relate to changes in 24-h than to
“office” BP and that clinical trials may underestimate the
impact of intrapatient variability in BP reduction on LVM
changes (22,23). However, these studies have studied patients selected based on elevated baseline BP, while in our
trial a history of hypertension was present in only 33% of the
study participants, and BP was, on average, well-controlled,
131/76 mm Hg.
Lonn et al.
Ramipril Improves LV Structure and Function
2205
The mean difference in change over four years in LVMI
between the placebo and ramipril 10 mg/day groups was 6
g/m2, which is less than observed in some BP-lowering
trials (22). However, such trials have selected patients who
were hypertensive and had baseline LV hypertrophy, while,
in our study, patient selection was based on cardiovascular
risk alone, and most patients had average (“normal”) baseline BP and LVM.
Our findings are concordant with other analyses of the
HOPE trial and with previous investigations. Thus, in the
HOPE trial, ramipril caused prevention or regression of LV
hypertrophy defined on electrocardiography, an effect that
was largely independent of BP changes (24). Other clinical
trials have also shown regression of LV hypertrophy with
ACE inhibitors in hypertensive populations and some
(10,11,25), although not all such trials (22), suggest that, for
similar degrees of BP-lowering, these agents may be more
effective than other antihypertensive agents in reducing LV
hypertrophy.
The mechanism of reduction in LVM with ACE inhibitor therapy is likely multifactorial. Angiotensin II is a
potent vasoconstrictor, has positive inotropic actions on the
heart muscle, and can further affect cardiac hemodynamics
by potentiating the actions of the sympathetic nervous
system (13,14). In addition, both circulating and locally
produced angiotensin II has a direct trophic effect on
myocardial smooth muscle cells and contributes to restructuring and proliferation of the myocardial extracellular
collagen matrix, thus promoting LV hypertrophy. The
ACE inhibitors can prevent or regress LV hypertrophy
through hemodynamic afterload reducing actions, but also
through load-independent mechanisms, as shown in animal
models (13,14,26,27).
The reduction in LV volume and the preservation of LV
systolic function observed in our study are also consistent
with the reduced rates of heart failure in the parent HOPE
trial (28) and with previous studies (8,12) and is related to
the hemodynamic afterload-reducing effect of ramipril, but
also to the prevention of new infarcts, to the benefit on
myocardial remodeling, and to the general stabilizing effect
of ACE inhibition on atherosclerosis (13,15). As shown in
experimental studies, these effects are related to blockade of
angiotensin II type 1 receptor-mediated actions, but also to
increased availability of bradykinin and possibly additional
ACE inhibitor effects (13–15,29).
In summary, our study shows a significant dosedependent, but, at least in part, BP-independent beneficial
effect of ACE inhibitor therapy on LV structure and
function. These results parallel similar findings on the
prevention of clinical events with ramipril observed in the
parent HOPE trial, which was only partly explained by BP
reduction. These data provide further evidence supporting
the use of long-term ACE inhibitor therapy in a wide range
of patients with cardiovascular disease.
2206
Lonn et al.
Ramipril Improves LV Structure and Function
Reprint requests and correspondence: Dr. Eva Lonn, Hamilton
Health Sciences Corporation, General Site, 237 Barton Street East,
Hamilton, Ontario, Canada, L8L 2X2. E-mail: lonnem@
mcmaster.ca.
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