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AJH 2007; 20:990 –996

Heart

Regression of Left-Ventricular Hypertrophy in


Children and Adolescents With Hypertension
During Ramipril Monotherapy

Tomáš Seeman, Jiřı́ Gilı́k, Karel Vondrák, Eva Šimková, Hana Flögelová,
Marie Hladı́ková, and Jan Janda

Background: Left-ventricular hypertrophy (LVH) is a 55.8 g/m2.7) to 32.6 g/m2.7 (range, 19.0 to 52.1 g/m2.7; P ⬍
risk factor for cardiovascular morbidity. Antihypertensive .05) after 6 months. The prevalence of LVH decreased
treatment with angiotensin-converting enzyme inhibitors from 42% to 11% using the pediatric definition (P ⬍ .05)
(ACEI) is able to induce the regression of LVH in adults. and did not change using the adult definition (ie, it re-
However, there has been no study of the ability of ACEI mained at 5%). The median ambulatory BP decreased by
to induce the regression of LVH in children. Our aim was 11, 7, 8, and 7 mm Hg for daytime systolic, daytime
to investigate the effect of ramipril on left-ventricular mass diastolic, nighttime systolic, and nighttime diastolic BP
and blood pressure (BP) in hypertensive children. (P ⬍ .05), respectively. A positive correlation was found
Methods: Twenty-one children (median age, 15 years) between LVMI and nighttime systolic BP at the start of the
with renal (76%) or primary (24%) hypertension were pro- study (r ⫽ 0.46, P ⬍ .05).
spectively treated with ramipril monotherapy for 6 months. Conclusions: Ramipril is an effective drug in chil-
Blood pressure was evaluated using ambulatory BP monitor- dren with hypertension, for its ability to reduce not only
ing, with hypertension defined as mean BP ⱖ95th percentile. BP but also left-ventricular mass and induce regression
Left-ventricular hypertrophy was defined either as left-ven- of LVH. Am J Hypertens 2007;20:990 –996 © 2007
tricular mass index (LVMI) ⬎38.6 g/m2.7 (pediatric defini- American Journal of Hypertension, Ltd.
tion) or as LVMI ⬎51.0 g/m2.7 (adult definition).
Results: Nineteen children completed the study. The Key Words: Left-ventricular hypertrophy, regression,
median LVMI decreased from 36.8 g/m2.7 (range, 18.9 to ramipril, children, hypertension.

eft-ventricular hypertrophy (LVH) is an important Left-ventricular hypertrophy is also a form of target-

L sequela of hypertension and an independent risk


factor for cardiovascular morbidity and mortality in
adult patients with hypertension.1,2 Regression of LVH is
organ damage frequently seen in hypertensive children; it
occurs in 8% to 41% of subjects.9 –12 Contrary to the case
with adults, there are no prospective studies showing that
associated with decreased cardiovascular risk.3,4 There- antihypertensive therapy can induce regression of LVH in
fore, regression of LVH has become one of the goals of children with hypertension. Only case reports showing that
antihypertensive therapy in adults.5 The regression of regression of LVH is possible in hypertensive children
LVH during antihypertensive therapy was well docu- have been published.13
mented in adult hypertensive patients with primary and The aim of our prospective interventional study was to
renal hypertension.3,6,7 Ambulatory blood-pressure moni- investigate the effect of ramipril treatment on left-ventric-
toring (ABPM) is superior to office blood pressure (BP) in ular mass and the prevalence of LVH in children with
predicting the treatment-induced regression of LVH.8 primary and secondary hypertension.

Received December 4, 2006. First decision January 1, 2007. Accepted Supported by Grants 0021620819 and 0006420301 from the Min-
March 11, 2007. istry of Education and Health of the Czech Republic VZ MŠMT and
From the Department of Pediatrics, and Kardiocentrum and Center VZMZ.
for Cardiovascular Research, University Hospital Motol, Second School Address correspondence and reprint requests to Dr. Tomáš Seeman,
of Medicine, Charles University, Prague, Czech Republic; Department of Department of Pediatrics, Second School of Medicine, Charles Univer-
Pediatrics, Palacky University, Olomouc, Czech Republic; and Department sity, V Uvalu 84, 15006 Prague 5, Czech Republic; e-mail: tomas.
of Medical Informatics, Charles University, Prague, Czech Republic. seeman@lfmotol.cuni.cz

0895-7061/07/$32.00 © 2007 by the American Journal of Hypertension, Ltd.


doi:10.1016/j.amjhyper.2007.03.009 Published by Elsevier Inc.
AJH–September 2007–VOL. 20, NO. 9 REGRESSION OF LVH IN CHILDREN WITH RAMIPRIL 991

Methods The intraobserver reliability of echocardiographic mea-


Study Population surements was adequate, insofar as the difference of re-
peated measurements of LVM in the same patient under
Twenty-one children and adolescents (median age, 15 similar conditions was 1.197 ⫾ SEM of 1.901 (89.595 on
years; range, 3.3 to 17.8 years; 14 boys) who fulfilled the the first measurement and 88.397 on the second measure-
inclusion criteria (primary or renal hypertension confirmed ment). This difference was not statistically significant
by ABPM, echocardiography evaluation at the time of (P ⫽ .53, 95% confidence interval for differences of
ABPM, and no treatment with antihypertensive agents) means, ⫺2.659 to 5.053).
were included in this prospective study. They were se- The glomerular filtration rate was classified according
lected consecutively over a period of 4 years (2001 to to National Kidney Foundation guidelines.21 It was normal
2004) in our two centers. The children were prospectively (calculated creatinine clearance according to the formula
treated for 6 months with ramipril monotherapy. No child of Schwartz et al,22 ⱖ90 mL/min/1.73 m2) in all children
received any other treatment for primary renal disease with primary hypertension and in 12 children with renal
other than ramipril (no steroids and no immunosuppres- hypertension, mildly reduced (creatinine clearance, 60 to
sive drugs). Ten children had already been included and 89 mL/min/1.73 m2) in 4 children, and moderately re-
evaluated in our previous study, which investigated the duced (creatinine clearance, 30 to 59 mL/min/1.73 m2) in
effect of ramipril on ambulatory BP and proteinuria in 1 child. Body mass index (BMI) was expressed in absolute
children with chronic kidney diseases.14 Four children had values (kg/m2) and in percentiles of the healthy Czech
primary hypertension, and 17 children had renal hyperten- child population.23 Overweight was defined as a BMI
sion. Primary renal diseases included polycystic kidney ⬎85th percentile (six children, 29%) and obesity as BMI
diseases (n ⫽ 8; autosomal-dominant polycystic kidney ⬎95th percentile (four children, 19%).
disease in 5 children and autosomal-recessive polycys- Ramipril was given as a single daily oral dose in the
tic kidney disease in 3 children), reflux nephropathy morning or in the evening (one child). The initial dose was
(n ⫽ 5), renal dysplasia (n ⫽ 2), residual renal abnor- 1.5 mg/m2/day. This dose was doubled if all mean BP
malities after hemolytic uremic syndrome (n ⫽ 1), and values were not ⬍95th percentile after 1 month of treat-
IgA nephropathy (n ⫽ 1). ment. The maximal dose was 6 mg/m2/day. Ramipril was
Ambulatory BP was measured by ABPM, using an oscil- given for 6 months as monotherapy. The ABPM and blood
lometric device (SpaceLabs 90207 or 90217; SpaceLabs, tests for serum creatinine, serum potassium, and blood
Redmond, WA). A cuff of an appropriate width for the arm count (by standard methods) were performed 1 month
circumference was chosen. Blood pressure was automati- after the initiation of treatment, 1 month after each change
cally recorded every 20 min during the day and every 30 of ramipril dose, and at the end of the study. Echocardi-
min at night. A record of daily activities and sleep during ography was performed at the end of the study (at 6
the night was obtained for each child. Hypertension was months). Patients were monitored at every outpatient visit
defined as a mean ambulatory systolic or diastolic BP during for the presence of adverse effects of ramipril, such as
the daytime or nighttime period ⱖ95th percentile for healthy cough, abdominal pain, fatigue, dizziness, orthostasis,
mid-European children.15 The nocturnal BP dip was calcu- edema, or rash. All parents gave informed consent for their
lated as a percentage of mean nighttime BP decline compared children to participate in the study, which was approved by
with mean daytime BP. The office BP was measured in the the local ethics committee.
renal clinic under standard recommended conditions, using a
mercury sphygmomanometer and an appropriate cuff.16
A standard two-dimensional echocardiogram (GE/ Statistics
Wingmed System 5; Vivid 7, Horten, Norway) was per- The data are expressed as medians and range. The Wil-
formed by one experienced pediatric cardiologist (JG) on coxon signed rank test and McNemar test were used to
the same day as ABPM, according to the recommenda- assess significant changes in follow-up. The correlations
tions of the American Society of Echocardiography.17 between variables (ambulatory BP, office BP, LVMI,
Left-ventricular mass (LVM) was calculated according to BMI, and glomerular filtration rate) were assessed by
the formula of Devereux et al from the left-ventricular Spearman correlation analysis (univariate and multivariate
internal dimension at end diastole, interventricular sep- analysis). P ⬍ .05 was regarded as statistically significant.
tal thickness, and left-ventricular posterior wall thick-
ness.18 Left-ventricular mass was indexed to height2.7
(left-ventricular mass index, LVMI) to account for body Results
size.19 Left-ventricular hypertrophy was defined either
Patients
as LVMI ⬎38.6 g/m2.7, which corresponds with the
95th percentile of normative pediatric LVMI data,19 or Nineteen children completed the 6-month study. The rea-
as LVMI ⬎51.0 g/m2.7, which in adults was found to sons for the two dropouts were noncompliance with the
correlate with a fourfold greater risk of cardiovascular study medication (n ⫽ 1) and missing the echocardiogra-
events.20 phy evaluation at the end of the study (n ⫽ 1).
992 REGRESSION OF LVH IN CHILDREN WITH RAMIPRIL AJH–September 2007–VOL. 20, NO. 9

Table 1. Baseline characteristics of patients children. The median ramipril dose at the end of the study
was 2.9 mg/m2/day (range, 1.1 to 5.7 mg/m2/day). The
Median (range) or percentage of nighttime dip in systolic BP decreased by
Variable number of patients 2% (the systolic BP dip changed from 10% at the start of
Age (y) 15.0 (3.3–17.8) the study to 8% at the end of the study). The percentage of
Sex (male/female) 14/7 nighttime dip in diastolic BP decreased by 1% (the dia-
BMI, absolute (g/m2) 21 (14.8–30.5) stolic BP dip changed from 18% to 17%). These differ-
BMI, relative (percentile) 63 (15–99)
Renal hypertension 17
ences were not statistically significant.
Primary hypertension 4
Creatinine clearance
(mL/min/1.73m2) 113 (55–245)
Echocardiography
Serum potassium Left-ventricular hypertrophy was present at the start of the
(mmol/L) 4.4 (3.6–5.0)
study in 42% of the children (8 of 19 children), using the
BMI ⫽ body mass index. 95th percentile of normative pediatric LVMI data for our
definition, and in 5% (one child), using the adult defini-
tion. At the end of the 6-month study, the prevalence of
LVH decreased significantly to 11% of the children (2 of
Blood Pressure
19 children), using the 95th percentile of normative pedi-
After 6 months of ramipril treatment, the mean daytime atric LVMI data as our definition (P ⬍ .05), and did not
systolic as well as nighttime diastolic BP decreased in 17 change (5%, one child, other than at the start) using the
of 19 children, the mean nighttime systolic BP decreased adult definition. The data are summarized in Fig. 1.
in all children, and the mean daytime diastolic BP de- The median LVMI decreased significantly after 6
creased in 14 children. The changes in ambulatory and months of ramipril treatment (data given in Table 2).
office BP after ramipril treatment are shown in Table 1. Individual values of LVMI before and at the end of the
Hypertension normalized (ie, all mean ambulatory BP study are given in Fig. 2.
values ⬍95th percentile) in 53% of children. The initial Using univariate analysis, there was no significant cor-
dose of ramipril had to be increased during the study in 12 relation between LVMI and daytime or nighttime systolic

FIG. 1. Effect of ramipril on the prevalence of hypertension (HT) and left-ventricular hypertrophy (LVH), using 95th percentile of normative
pediatric left-ventricular mass index (LVMI) data for definition of LVH.
AJH–September 2007–VOL. 20, NO. 9 REGRESSION OF LVH IN CHILDREN WITH RAMIPRIL 993

Table 2. Change in left-ventricular dimensions and blood pressure in ramipril-treated patients*

P
Variable Baseline After 6 months value
Mean ambulatory daytime
systolic BP (mm Hg) 133.0 (112–154) 124.4 (110–142) ⬍.001
Mean ambulatory daytime
diastolic BP (mm Hg) 80.0 (67–109) 74.3 (65–90) ⬍.01
Mean ambulatory nighttime
systolic BP (mm Hg) 120.0 (109–138) 111.0 (97–125) ⬍.001
Mean ambulatory nighttime
diastolic BP (mm Hg) 69.0 (53–89) 61.0 (51–72) ⬍.001
Mean ambulatory 24-h systolic
BP (mm Hg) 125.5 (112–146) 115.5 (106–134) ⬍.001
Mean ambulatory 24-hr diastolic
BP (mm Hg) 74.5 (64–99) 66.5 (60–81) ⬍.001
Office systolic BP (mm Hg) 135.0 (110–160) 130.0 (102–160) NS
Office diastolic BP (mm Hg) 86.0 (70–110) 85.0 (60–100) NS
LVMI (g/m2.7) 37.4 (18.8–55.8), 36.2 ⫾ 8.6 32.5 (19.0–52.1), 33.1 ⫾ 7.2 ⬍.05
IVS thickness (cm) 0.72 (0.39–1.08) 0.68 (0.54–1.08) NS
LVPW thickness (cm) 0.78 (0.57–1.04) 0.78 (0.55–0.96) NS
LVID (cm) 4.82 (3.16–5.58) 4.75 (2.69–5.77) NS
RWT 0.31 (0.21–0.41) 0.30 (0.21–0.46) NS

BP ⫽ blood pressure; IVS ⫽ interventricular septum; LVID ⫽ left-ventricular internal dimension; LVMI ⫽ left-ventricular mass index; LVPW
⫽ left-ventricular posterior wall; NS ⫽ not significant; RWT ⫽ relative wall thickness.
* Values are median (range), if not given as mean ⫾ SD.

or diastolic BP. No significant correlation was found be- changes in daytime or nighttime systolic or diastolic BP,
tween LVMI and renal function or BMI. No significant changes in renal function, or changes in BMI during the
correlation was found between changes in LVMI and study. The correlations with a trend toward a significant

FIG. 2. Effect of ramipril on left-ventricular mass index (LVMI) in individual patients.


994 REGRESSION OF LVH IN CHILDREN WITH RAMIPRIL AJH–September 2007–VOL. 20, NO. 9

FIG. 3. Correlation between left-ventricular blood pressure (LVMI) and nighttime systolic blood pressure. BP ⫽ blood pressure; LVH ⫽
left-ventricular hypertrophy. On the x axis, nighttime systolic BP in mmHg in relation to 95th percentile (0 ⫽ 95th percentile, according to
Soergel et al15).

relationship were correlations between LVMI and night- veloped mild hyperkalemia (5.3 and 5.6 mmol/L) at the
time systolic BP (r ⫽ 0.42, P ⫽ .07), BMI in percentiles final outpatient check at 6 months, which normalized by
(r ⫽ 0.43, P ⫽ .06), daytime systolic BP (r ⫽ 0.37, P ⫽ adding a diuretic after completing the 6-month study pro-
.12), and 24-h systolic BP at the start of the study (r ⫽ tocol. One child who developed hyperkalemia had mod-
0.32, P ⫽ .17), and between the change in LVMI and erately decreased renal function (55 mL/min/1.73 m2), and
the change in daytime systolic BP during the study (r ⫽ the second already had a high-normal potassium level at
0.39, P ⫽ .10). Using multivariate analysis, there was a baseline (4.7 mmol/L). No significant change in hemoglo-
significant correlation only between LVMI and night- bin level was noted (a decrease by 1 g/L).
time systolic BP at the start of the study (r ⫽ 0.46, P ⫽
.048, Fig. 3). Discussion
In our previous study, we showed that ramipril is a safe
Renal Function, BMI, and Side Effects
and effective drug for the treatment of hypertension and
At the end of the study, the glomerular filtration rate did proteinuria in children with chronic kidney diseases.14 Our
not change significantly. The median glomerular filtration current study is the first prospective, interventional trial on
rate decreased from 113 mL/min/1.73 m2 (range, 55 to 245 the effects of ramipril on LVM and the prevalence of LVH
mL/min/1.73 m2) to 107 mL/min/1.73 m2 (range, 54 to in children with primary and renal hypertension. We were
195 mL/min/1.73 m2). Body mass index did not change able to demonstrate that 6-month ramipril monotherapy
significantly: the median relative BMI increased from the can induce a significant reduction of LVM and a regres-
63rd percentile (range, 16th to 99th percentile) to the 67th sion of LVH in three-quarters of the hypertensive children
percentile (range, 6th to 98th percentile); the median ab- treated.
solute BMI was 21.0 kg/m2 (range, 14.8 to 30.5 kg/m2) at Left-ventricular hypertrophy is an independent predic-
the start of the study and 21.2 kg/m2 (range, 14.8 to 30.1 tor of cardiovascular morbidity and mortality in adults.1,2
kg/m2) at the end of the study. Ramipril was well tolerated Moreover, regression of LVH is associated with fewer
by the children; no child complained of a cough. The cardiovascular events.24 Therefore, LVH is becoming an
median serum potassium level did not change significantly important treatment goal for hypertensive patients.5,25 All
(a decrease by 0.1 mmol/L). However, two children de- classes of antihypertensive drugs are able to reduce LVH.
AJH–September 2007–VOL. 20, NO. 9 REGRESSION OF LVH IN CHILDREN WITH RAMIPRIL 995

However, drugs blocking the renin-angiotensin systems, between change in daytime systolic BP and change in
such as angiotensin-converting enzyme (ACE) inhibitors LVMI was noted. Furthermore, since no significant corre-
or angiotensin receptor blockers (ARBs) (eg, as used in the lation with BP was found with other determinants of
HOPE and LIFE trials), seem to have some benefits be- LVM, such as BMI, renal function, or hemoglobin level,
yond the BP-lowering effects on regression of LVH in we can speculate that a part of the regression of LVH may
comparison to other antihypertensive agents.24 be caused by BP-independent mechanisms because of
In children, LVH is also a prevalent cardiovascular ACE inhibition.34
consequence of hypertension, affecting 8% to 41% of Despite the beneficial effect on the prevalence of LVH
hypertensive children,9 –12,26,27 and 33% to 75% of chil- (reduction from 42% to 11%), almost half of the children
dren with chronic renal insufficiency, and children on remained hypertensive at the end of the 6-month period of
dialysis or after renal transplantation.28 –30 Because most ramipril monotherapy. To achieve better BP control, about
of the children in our study had renal hypertension, it must half of the hypertensive children will require a combina-
be emphasized that children with renal hypertension have tion of antihypertensive agents. Further studies are war-
a higher prevalence of LVH than children with primary ranted to test whether tighter BP control by combination
hypertension. Therefore, the relatively high LVH preva- therapy will result in further regression of LVH.
lence of 42% in our study is due to the great majority of Ramipril was very well tolerated by the children in our
children having chronic kidney disease. Blood pressure study. We did not observe cough in any child. Mild
and BMI are the most important determinants of LVH in
hyperkalemia was detected in only two children: one of
children.31 We found a correlation between nighttime sys-
them had moderately decreased renal function, which is a
tolic BP and LVMI using multivariate analysis. In con-
known risk factor for the development of hyperkalemia
trast, we could not find any correlation between diastolic
during therapy with ACE inhibitors, and the second child
BP, daytime systolic BP, or BMI and LVMI, which is in
already had a high-normal potassium level at the start of
accordance with other cross-sectional studies28 but in con-
the study. Therefore, children with decreased renal func-
trast to other studies showing a correlation between am-
tion or high-normal potassium levels should be checked
bulatory BP and LVMI.27 However, a nonsignificant trend
for a relationship between daytime and 24-h systolic BP frequently for hyperkalemia during treatment with ACE
and BMI and LVMI was noted in our study, suggesting inhibitors. The hyperkalemia normalized after adding
that systolic BP and body composition influence LVM in diuretics at the end of the 6-month study period. No
hypertension children. significant effects on renal function or hemoglobin level
In children with chronic renal failure (ie, those with were observed.
predialysis, dialysis, and transplants), several studies dem- The limitations of our study were mainly its uncon-
onstrated that the regression of LVH is possible through trolled and nonblind design and the lack of a comparison
strict BP treatment and by achieving correct dry weight drug. However, our study was not designed to compare
and avoiding hyperhydration.32,33 However, for children different drugs but to demonstrate that regression of LVH
with primary or renal hypertension without chronic renal by antihypertensive therapy with an ACE inhibitor is
failure, there are no studies investigating the effects of possible in children with primary hypertension and renal
antihypertensive therapy on LVM and on the prevalence hypertension without chronic renal failure. A further lim-
of LVH. Our study clearly demonstrates that BP reduction itation of our study is the small number of patients, which
by ramipril also leads to a reduction of LVH after 6 makes the study insufficiently powered to detect differ-
months in most children with primary hypertension and ences in several variables. Despite these limitations, this
renal hypertension without chronic renal failure. It must be study provides the first prospective, interventional pediat-
stated that the regression of LVH in patients with chronic ric trial on the effects of ramipril on LVM.
kidney diseases may be equally due to treatment of the In conclusion, ramipril is an effective and safe drug in
primary renal disease. However, in our study, no child children with hypertension that is able to reduce LVM and
received any treatment for primary renal disease other than induce regression of LVH.
ramipril (ie, no steroids or immunosuppressive drugs).
Several adult studies such as the HOPE and LIFE trials
showed that agents blocking the renin-angiotensin-aldo-
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