Author + information
- Received March 24, 1998
- Revision received December 30, 1999
- Accepted February 28, 2000
- Published online July 1, 2000.
- ↵*Reprint requests and correspondence: Dr. Yoshiki Mori, Department of Pediatric Cardiology, The Heart Institute of Japan, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinju-ku, Tokyo, Japan, 162-8666
This study examined whether long-term therapy with an angiotensin-converting enzyme (ACE) inhibitor reduces excessive increases in left ventricular (LV) mass as well as volume in growing children with aortic regurgitation or mitral regurgitation.
The ACE inhibitor reduces volume overload and LV hypertrophy in adults with aortic or mitral regurgitation.
This study included 24 patients whose ages ranged from 0.3 to 16 years at entry to the study. On echocardiography, we measured LV size, systolic function and mass. After obtaining baseline data, patients were allocated into two groups. Twelve patients were given an ACE inhibitor (ACE inhibitor group), and 12 patients were not (control group). Echo parameters were again assessed after an average 3.4 years of follow-up.
Left ventricular parameters at baseline in the two groups were similar. The Z value of LV end-diastolic dimensions decreased from +0.82 ± 0.55 to +0.57 ± 0.58 in the ACE inhibitor group, whereas it increased from +0.73 ± 0.85 to +1.14 ± 1.04 in the control group (mean change −0.25 ± 0.33 for the ACE inhibitor group vs. +0.42 ± 0.48 for the control group, p = 0.0007). The mass normalized to growth also reduced from 221 ± 93% to 149 ± 44% of normal in the ACE inhibitor group and increased from 167 ± 46% to 204 ± 59% of normal in the control group (mean change −72 ± 89% of normal for the ACE inhibitor group vs. +37 ± 35% of normal for the control group, p = 0.0007).
Long-term treatment with ACE inhibitors is effective in reducing not only LV volume overload but also LV hypertrophy in the hearts of growing children with LV volume overload.
Chronic volume overload leads to ventricular dilation and myocardial hypertrophy, which subsequently entails irreversible structural and functional damage through a process known as “cardiomyopathy of overload” (1,2). Therefore, it should be desirable to prevent development of excessive cardiac mass. In recent years, several investigators have reported that prophylactic administration of angiotensin-converting enzyme (ACE) inhibitor during the stable compensated plateau phase of a chronic volume overload form of heart disease reduces the extent of ventricular dilation and excessive mass (3–6) and improves left ventricular (LV) function (3,5). However, these studies have been limited to adult patients or older children, and there have been no data in growing children.
After birth, the heart normally increases in size and mass with development, and the growth of the ventricle is very rapid in the neonatal period (7,8) and gradually downregulated with maturation (9,10). Increasing evidence suggests that locally synthesized angiotensin II is related, at least partly if not all, to the normal growth of the left ventricle (7,9–11). Thus, the effects of ACE inhibition could theoretically be different in growing children. In the present study, we tested the hypothesis that long-term therapy with ACE inhibitor has beneficial effects on the growing left ventricle of pediatric patients with volume overloaded lesions.
Twenty-four patients with chronic LV volume load were enrolled in this long-term follow-up study. The median age of subjects was 3.9 years and ranged from four months to 16 years at entry to the study. All patients were asymptomatic but had moderate to severe cardiomegaly on chest roentogenogram. Sixteen patients had aortic regurgitation (AR) and eight patients had mitral regurgitation (MR). Within the AR group, 13 patients had transposition of the great arteries after the two-staged arterial switch operation, 2 patients had ventricular septal defect with right coronary cusp prolapse after intracardiac repair and 1 had congenital AR. In the MR group, four patients had atrioventricular canal defect after intracardiac repair and four patients had ventricular septal defect with MR after intracardiac repair. None had rheumatic carditis. Severity of regurgitation was graded by color Doppler flow mapping using the method described by Omoto et al. (12), and was severe in 5 patients, moderate in 14 patients and mild in 5 patients. The follow-up period was from 1.1 to 8.8 years (mean ± SD = 3.4 ± 2.0 years).
Initial evaluation included a complete history of symptoms, physical examination, 15-lead electrocardiogram, chest roentogenogram and two-dimensional echocardiographic study. Thirty-two patients with chronic LV volume overload initially were enrolled to the study. After the baseline data were obtained, the 32 patients were alternately and randomly allocated into two groups. One group was given an ACE inhibitor (ACE inhibitor group), and the other group was not (control group). The ACE inhibitor group initially consisted of 16 patients, including 4 patients who were eventually excluded from analysis because of paradoxical motion of interventricular septum in 3 and elevated right ventricular pressure (>40% of systemic pressure) in 1. The control group initially consisted of 16 patients, including 4 patients who were eventually excluded because of paradoxical motion of interventricular septum. The characteristics of the 24 patients are listed in Table 1. Echocardiographic evaluation was repeated at an average of 3.4 years of follow-up after allocation.
Cilazapril was given to nine patients and enalapril to three patients. Each ACE inhibitor was started with a low dose, which was increased to the final dose over 1 to 2 weeks. The final dosage of cilazapril was 0.03 to 0.04 mg/kg/day (maximum dosage 1.0 mg/day) and the final dose of enalapril was 0.15 to 0.4 mg/kg/day (maximum dosage 5 mg/day). This final dose was chosen based on our previous pharmacological study, which demonstrated that it would significantly reduce plasma angiotensin II and increase plasma renin activity (unpublished data).
Other conventional anticongestive drugs being administered were digoxin in one patient and diuretics in six patients in the ACE inhibitor group, and digoxin in one patient and diuretics in four patients in the control group (Table 1).
Measurements of LV end-diastolic and end-systolic dimensions and posterior wall thickness were made from two-dimensionally guided M-mode recordings. Three to five consecutive cardiac beats were measured according to the recommendations of the American Society of Echocardiography (13) and the mean values were taken. Serial measurements were made by an observer blinded to patient treatment status. Fractional shortening and mean velocity of circumferential fiber shortening corrected for heart rate were derived from the standard equations. To adjust for age- and growth-related changes in echocardiographic variables, LV dimensions and posterior wall thickness were expressed as a Z-value. The Z-value was calculated by comparing patient data with our own normal data from 110 Japanese infants and children. The formulas for LV dimension and posterior wall thickness were as follows: LV end-diastolic dimension = 35.1 log BSA + 40.8 (r = 0.92, SEE = 3.2 mm); LV end-systolic dimension = 22.0 log BSA + 26.1 (r = 0.87, SEE = 3.4 mm); posterior wall thickness = 4.1 log BSA + 6.1 (r = 0.85, SEE = 0.56 mm), where BSA is body surface area. LV muscle mass was calculated according to the method of Troy et al. (14) and was expressed as a percentage of normal.
Interobserver and intraobserver variability
To evaluate the effect of inter- and intraobserver variability on the measurements of LV dimensions and posterior wall thickness, 15 randomly selected patients were analyzed at different times independently by one researcher (Y.M.) and an expert technician from our echo laboratory, who had no knowledge of the patients’ treatment or the results obtained by the other observer. Measurements were repeated by the same researcher at least two weeks later to evaluate intraobserver variability.
Values were expressed as mean ± SD. Wilcoxon rank sum test and Fisher’s exact test were used for comparisons of the two groups’ baseline data. The significance of treatment effect was determined by comparing the two groups using two-way repeated-measures analysis of variance (ANOVA). In addition, a two independent sample t test was used for comparisons of change from baseline between the two groups. A p value < 0.05 was considered statistically significant. Correlation coefficients were used to compare the two independent observers’ and intraobserver’s measurements.
Baseline comparisons and follow-up
Clinical characteristics of the subjects and follow-up period, and measurements of LV dimensions and function at baseline, were similar between the two groups. While the number of patients with AR was greater in the control group than in the ACE group, the difference in incidence was not statistically significant (Table 1). There were no patients who had side effects or withdrew from the therapy in the ACE inhibitor group. All study patients were asymptomatic and none required surgical intervention during the follow-up period.
Effects of ACE inhibitor on echocardiographic parameters
The results of the two-way repeated-measures ANOVA for group and time are summarized in Table 2. The two-way ANOVA showed that there was no overall significant difference in the mean values of the LV parameters between the two groups (p > 0.05 for each LV parameter) or the two time periods (p > 0.05 for each LV parameter) (Table 2). However, there was a significant interaction in the change of all LV parameters but not mean velocity of circumferential fiber shortening corrected for heart rate (Table 2). In order to improve the description of the significant interaction between group and time (for all outcomes except mean velocity of circumferential fiber shortening corrected for heart rate), the mean change from baseline is presented for each group along with the two independent sample t tests (Table 3). This test is approximately the same as the test for interaction, as evidenced by the close correspondence of the t test p values and interaction values from the ANOVA model. This is illustrated in Figures 1 and 2 by a negative slope for the ACE inhibitor group and a positive slope for the control group. ⇓⇓ Thus, growth-adjusted LV end-diastolic dimensions decreased from baseline in the ACE inhibitor group over the study period (Z value +0.82 ± 0.55 at baseline vs. +0.57 ± 0.58 at follow-up), and they increased from baseline in the control group (+0.73 ± 0.85 at baseline vs. +1.14 ± 1.04 at follow-up). LV end-systolic dimensions also decreased in the ACE inhibitor group (Z value +0.90 ± 0.54 at baseline vs. +0.54 ± 0.63 at follow-up), whereas they increased in the control group (+0.72 ± 0.76 at baseline vs. +1.18 ± 0.90 at follow-up) (Fig. 1). There was a significant difference in the change of LV end-diastolic dimensions and systolic dimensions from baseline to follow-up between the two groups (p = 0.0007 for the LV end-diastolic dimension, p = 0.0009 for the LV end-systolic dimension; Table 3).
Fractional shortening increased within the normal range in the ACE inhibitor group (0.30 ± 0.07 at baseline vs. 0.34 ± 0.06 at follow-up), and decreased in the control group (0.33 ± 0.06 at baseline vs. 0.31 ± 0.05 at follow-up). There was also a significant difference in the change from baseline between the two groups (p = 0.02; Table 3). However, mean velocity of circumferential fiber shortening corrected for heart rate stayed within the normal range in both groups (0.94 ± 0.21 at baseline vs. 1.02 ± 0.16 at follow-up in the ACE inhibitor group, 0.92 ± 0.20 at baseline vs. 0.89 ± 0.17 at follow-up in the control group), and there was not a significant difference in the change from baseline to follow-up between the two groups (p = 0.13; Table 3).
Posterior wall thickness adjusted for growth decreased from +0.54 ± 0.42 (Z-value) at baseline to +0.23 ± 0.38 at follow-up in the ACE inhibitor group, but it increased from +0.36 ± 0.28 at baseline to +0.67 ± 0.26 at follow-up in the control group (Fig. 2). Left ventricular muscle mass was 221 ± 93% of normal in the ACE inhibitor group and 167 ± 46% of normal in the control group at baseline. These baseline values were not statistically different between the two groups (p = 0.15). The LV muscle mass decreased from 221 ± 93% to 149 ± 44% of normal in the ACE inhibitor group, whereas it increased from 167 ± 46% to 204 ± 59% of normal in the control group (Fig. 2). There was also a significant difference in the change of posterior wall thickness and mass from baseline between the two groups (p = 0.0004 for the posterior wall thickness, p = 0.0007 for the LV mass; Table 3).
Interobserver and intraobserver variability
Excellent correlations were found between the two independent observers’ measurements of LV dimensions (r = 0.97, SEE = 3 mm, p < 0.0001) and posterior wall thickness (r = 0.94, SEE = 0.73 mm, p < 0.0001). The intraobserver variability was also acceptable for LV dimensions (r = 0.98, SEE = 2.3 mm, p < 0.0001) and for posterior wall thickness (r = 0.96, SEE = 0.51 mm, p < 0.0001).
Treatment with ACE inhibitors acutely reduces regurgitant volume and improves cardiac performance in AR (15,16) and MR (17), and chronically decreases LV volume and hypertrophy in adult patients with AR (3,4) and in dogs with MR (5). These studies were performed only in adults, and a recent study of Alehan et al. (6) demonstrated that one year of captopril therapy significantly reduced LV volume and mass in children or adolescents with AR, whose mean age, however, was 14 years. A few studies in pediatric patients (18,19) have suggested that the benefits of ACE inhibition in children may be similar to adult patients, but they did not test its long-term effect. Thus, there has been virtually no data on long-term efficacy of ACE inhibitors in growing children.
Our study showed that the volume overload itself increased body size-adjusted LV dimensions and muscle mass progressively, while children were still growing. These findings are in striking contrast to the results in adult patients, which showed that these parameters did not change during 12 to 24 months in patients with AR without vasodilator therapy (20,21). Although the follow-up period between their studies and our study was different, we suspect that the increase in LV volume and mass in our controls may be specific for growing children.
It has been demonstrated that a rapid growth of the left ventricle normally occurs in the neonatal period (7,8) and the capacity of myocardial remodeling secondary to volume overload is enhanced during the growth period (22), and these characteristics are gradually downregulated (9,10,22). Angiotensin II is one of the important factors for stimulation of normal growth of the heart during childhood as well as pathological dilatation and hypertrophy (7,9–11,23–27). In fact, previous studies have shown that ventricular angiotensin II mRNA level (10) and density of angiotensin II receptors (9,10) are significantly higher at the neonatal or growing period than at the late developmental period, and they are again downregulated with maturation (10). These studies indicate that the cardiac renin-angiotensin system may have played an important role in the significant increase in LV size and muscle mass observed in our control patients.
The more important finding in our study was that ACE inhibitor treatment prevented development of excessive LV muscle mass or even reduced LV muscle mass. ACE inhibitors are a potent vasodilator and reduce volume load to the heart, as shown in the previous acute studies (15,16). This mechanism could be one of the factors related to our finding. Because we did not compare the effect of ACE inhibitors with other vasodilators in the present study, we cannot conclude that only ACE inhibition reduces LV muscle mass in growing children with regurgitant lesions. However, it has been shown in animal studies that ACE inhibitors can reduce hypertrophy by a process that is independent of systemic hemodynamics (25,28–31), and the renin-angiotensin system is known to be highly relevant in remodeling of the growing heart as described above. Therefore, the reduction of LV muscle mass would be largely a result of inhibition of the renin-angiotensin system. Regardless of precise mechanisms, all of these effects, alone or in combination with each other, could explain the prevention of excessive muscle mass development produced by LV volume overload. Progressive ventricular dilation and increase in muscle mass are important predictors of the need for surgical intervention. The results of our study suggest that ACE inhibitor therapy could delay deleterious structural changes of the LV myocardium and thus postpone surgical intervention.
Our study has several limitations that must be recognized. First, we included patients with both AR and MR. Also, by the random selection basis of our LV volume overload patients and the small patient numbers, AR was more frequent in the control group than in the ACE inhibitor group. It has been reported that AR may have a different natural history from MR in adults (32–34). A cross-over study would be able to overcome this limitation. However, as the study progressed, we found a significantly better outcome in the ACE inhibitor group, and therefore we did not feel that it was appropriate or ethical to perform a cross-over study in the light of our preliminary data. Second, our follow-up period may not be long enough to draw a firm conclusion, although three years of follow-up is comparable with the previous studies of similar design (3,4,6). Furthermore, it would have been highly desirable to increase the number of patients in our study, but it was not practical in one institute because isolated significant aortic or mitral regurgitation is rather rare in young children. Multicenter studies will be required to increase the number of patients for a randomized, double-blinded study.
Our study suggests that long-term treatment with ACE inhibitor is effective in reducing not only LV volume but also LV hypertrophy in the volume-overloaded heart of growing children. Further study is necessary to demonstrate whether ACE inhibitor treatment specifically improves the natural history and facilitates delaying heart surgery in children with aortic or mitral regurgitation.
The authors thank David J. Sahn, MD, FACC of the Oregon Health Sciences University for critical comments and assistance in preparing this manuscript, Dale Kraemer, PhD of the Oregon Health Sciences University for assistance in statistical analysis and Noriko Kikuchi and Yoshinori Tsuruta (technicians in our echo laboratory) for technical help.
- angiotensin-converting enzyme
- analysis of variance
- aortic regurgitation
- left ventricular
- mitral regurgitation
- Received March 24, 1998.
- Revision received December 30, 1999.
- Accepted February 28, 2000.
- American College of Cardiology
- Ross J. Jr.
- Katz A.M.
- Schön H.R.,
- Dorn R.,
- Barthel P.,
- Schömig A.
- Lin M.,
- Chiang H.T.,
- Lin S.L.,
- et al.
- Suzuki J.,
- Matubara H.,
- Urakami M.,
- Inada M.
- Sahn D.J.,
- DeMaria A.,
- Kisslo J.,
- Weyman A.
- Troy B.L.,
- Pombo J.,
- Rackley C.E.
- Reske S.N.,
- Heck I.,
- Kropp J.,
- et al.
- Gay R.G.
- Seguchi M.,
- Nakazawa M.,
- Momma K.
- Greenberg B.,
- Massie B.,
- Bristow J.D.,
- et al.
- Scognamiglio R.,
- Fasoli G.,
- Ponchia A.,
- Dalla-Volta S.
- Lindpaintner K.,
- Ganten D.
- Sadoshima J.,
- Izumo S.
- Brown N.J.,
- Vaughan D.E.
- Baker K.M.,
- Chernin M.I.,
- Wixon S.K.,
- Aceto J.F.
- Baker K.M.,
- Aceto J.F.
- Bonow R.O.,
- Lakatos E.,
- Maron B.J.,
- Ebstein S.E.