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Endothelial Function, Carotid Artery Intima-Media Thickness, Epicardial Adipose Tissue, and Left Ventricular Mass and Function in Growth Hormone-Deficient Adolescents: Apparent Effects of Growth Hormone Treatment on These Parameters

Pediatric Endocrine Unit and División of Pediatric Cardiology, Hospital de Clinicas Caracas, 1010 Caracas, Venezuela; and Division of Endocrinology, Hospital Central Dr. Carlos Arvelo, 1010 Caracas, Venezuela

Address all correspondence and requests for reprints to: Roberto Lanes, M.D., M-209, P.O. Box 020010, Miami, Florida 33102. E-mail: lanes{at}telcel.net.ve.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Objective: The purpose of this study was to determine whether GH-deficient (GHD) adolescents have abnormalities of cardiac and vascular function detectable during the teenage years.

Design/Methods: Ten GHD children on GH treatment with a chronological age (CA) of 14.6 ± 1.7 yr and 12 untreated GHD adolescents with a CA of 15.0 ± 3.0 yr were studied. Cardiac mass and function, carotid artery intima-media thickness, flow-mediated endothelium-dependent vasodilation (percent change from baseline diameter during hyperemia), and hyperemia-induced blood flow increase of the brachial artery (percent change from baseline) and epicardial adipose tissue were evaluated by echocardiography. Fourteen healthy adolescents served as controls.

Results: Untreated GHD adolescents present with a reduced left ventricular mass when compared with controls (P < 0.05) and a lower flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia than both controls and treated GHD subjects (P < 0.02), whereas their epicardial adipose tissue is significantly higher than that of healthy controls (P < 0.02). Interventricular septum thickness, posterior wall thickness, left ventricular ejection fraction, and carotid artery intima-media thickness were similar in all three groups. Hyperemia-induced blood flow increase was greater in treated GHD adolescents than both untreated subjects and controls (P < 0.001). Body mass index correlated positively with epicardial adipose tissue in all three groups and with carotid intima-media thickness in treated and untreated GHD adolescents.

Conclusions: GHD adolescents have a reduced left ventricular mass and vascular abnormalities manifested by lower flow-mediated endothelium-dependent vasodilation. These findings together with an increase in epicardial adipose tissue, a good indicator of abdominal/visceral fat, may contribute to an increased cardiovascular risk in the long term. An improvement in endothelial function and a reduction in arterial stiffness appear to occur after GH replacement.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
SUBJECTS WITH GH deficiency (GHD) have been shown to have an increased cardiovascular risk as manifested by hyperlipidemia, an increase of body fat, premature atherosclerosis, decreased fibrinolytic activity, increased peripheral insulin resistance, increased frequency of impaired glucose tolerance, abnormal cardiac structure, and impaired cardiac performance (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). Short- and long-term GH treatment has been shown to exert beneficial effects on abdominal fat distribution, fasting, and postprandial lipid levels and enhance cardiac function, increase cardiac mass, and reverse diastolic abnormalities in adults with hypopituitarism and GHD (12, 13, 14, 15). Two recent studies (16, 17) reported that GHD in children affects heart morphology by inducing a significant decrease in cardiac size but without modifying cardiac function. An increase in left ventricular mass normalized for changes in body size was noted during the first year of GH treatment in GHD children (17).

Young GHD adults have been shown to have an increased number of atheromatous plaques in the carotid and femoral arteries. Increased intima-media thickness of the carotid arteries, increased stiffness of the carotid artery wall, and impaired flow-mediated endothelium-dependent dilation of the brachial artery have also been reported in this group of patients (18, 19). Inflammation plays an important role in the atherosclerotic process of the arterial wall, and peripheral markers of inflammatory activity such as C-reactive protein, TNF, and IL-6 have been shown to correlate with the risk of atherosclerosis in adults and adolescents with GHD (20, 21, 22) and to be independently associated with the degree of common carotid artery intima-media thickness in GHD adults (21). GH treatment of hypopituitary GHD adults has recently been found to reverse early morphological and functional atherosclerotic changes in major arteries and may be indicative of a beneficial effect of GH treatment on the vascular system (23, 24, 25). In a recent study, we were unable to find an increase in the intima-media thickness of the carotid arteries in untreated GHD adolescents when compared with that of treated GHD subjects or healthy controls, and this parameter has not been evaluated further in GHD children or adolescents (26). The flow-mediated endothelium-dependent dilation of the brachial artery has to our knowledge not been previously evaluated in GHD children or adolescents.

A very recent study in adults (27) has reported that the measurement of epicardial adipose tissue on the right ventricle by ultrasonography showed a very good correlation with magnetic resonance imaging of abdominal visceral adipose tissue and with epicardial fat measurement, so that echocardiographic epicardial adipose tissue could be used as a reliable and easy imaging indicator of visceral adipose tissue and cardiovascular risk. This parameter was found to be of value in the evaluation of adults with the metabolic syndrome but has not been previously used to study either GHD adults or children.

To evaluate the cardiovascular status of GHD adolescents, we measured cardiac mass and function, carotid intima-media thickness, flow-mediated endothelium-dependent dilation of the brachial artery, and epicardial adipose tissue by echocardiographic and Doppler studies in a group of GH-treated GHD adolescents, a group of untreated GHD adolescents, and a healthy control group.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Ten GHD adolescents on GH treatment, 12 untreated GHD adolescents, and 14 healthy controls were evaluated. Of the 10 treated GHD children, three were males and seven were females. These patients had a mean chronological age of 14.6 ± 1.7 yr, a mean bone age of 11.9 ± 2.4 yr, and a mean height of 146.1 ± 12.1 cm (height SD score of –2.4 ± 0.4). Six of the 10 patients had idiopathic, isolated GHD, whereas four subjects had organic GHD (two patients with a craniopharyngioma who had been treated with surgery and radiotherapy had multiple hormonal deficiencies, whereas the other two subjects, one with a hamartoma and the other one with anterior pituitary hypoplasia, had isolated GHD); seven subjects had entered puberty (Tanner stages 2–4). These subjects were on GH treatment for the last 3.8 ± 1.1 yr at a dose of 0.1 IU/kg·d (0.03 mg/kg·d). Of the 12 untreated GHD adolescents, there were six males and six females. They had a mean chronological age of 15.0 ± 3.0 yr, mean bone age 12.3 ± 2.4 yr, and a mean height of 145.1 ± 16.7 cm [height-SD score (SDS) of –2.9 ± 0.4]. Seven of the 12 subjects had idiopathic isolated GHD and five had organic GHD (three with a craniopharyngioma and one with a macroadenoma who had been treated with surgery and radiotherapy had multiple hormonal deficiencies, whereas the other one with anterior pituitary hypoplasia had isolated GHD); eight had entered puberty (Tanner stages 2–4). Four of the untreated GHD children had received GH in the past (shortly after diagnosis of GHD) at a dose of 0.1 IU/kg·d for a period of 1.6 ± 0.2 yr but were already off therapy at the time of the study for a mean of 3.4 ± 1.2 yr (due to their inability to either obtain this medication through the social security system or purchase it), whereas eight patients had never been treated with GH. Fourteen healthy adolescents (seven males and seven females) all comparable for bone age, body height, body mass index (BMI), pubertal status, blood pressure, and pulse participated in the study as controls. Baseline characteristics of these patients can be seen in Table 1

GHD had been diagnosed in all 22 patients a mean of 5.2 ± 1.9 yr before entry into the present study by means of two stimulation tests (clonidine and Larodopa; peak GH concentrations of 3.2 ± 2.4 and 3.0 ± 2.3 µg/liter, respectively; range of 0.9–5.6 µg/liter) as well as reduced IGF-I and IGFBP3 levels for age [92.4 ± 21.3 ng/ml (–1.9 ± 0.6 SDS) and 2318.3 ± 583.3 ng/ml (–1.8 ± 0.4 SDS); normal values for age 498 ± 134 ng/ml for IGF-I and 4492 ± 1280 ng/ml for IGFBP3]. None of the patients was obese, and each had a normal BMI for age of between 15 and 25 kg/m². All patients had normal blood pressures and pulse as well as normal serum cortisol, prolactin, and thyroid function tests at the time of the study; LH, FSH, and testosterone/estradiol levels were appropriate for pubertal status (patients with multiple hormone deficiencies were receiving replacement therapy for their missing hormones).

Echocardiography was performed by a pediatric cardiologist and his technician who were blinded to the status of the patients studied (GHD vs. control; treated vs. untreated). Transthoracic echocardiographic measurements were performed with a Philips Sonos 5500 machine (Bothell, MA) using a 3.0-mHz transducer for two-dimensional M-mode measurements of the left ventricular mass and a linear 3.0- to 11-mHz transducer for the vascular studies according to the recommendations of the American Society of Echocardiography (30). M-mode echocardiography was used to measure left atrial and ventricular dimensions and left ventricular wall thickness, allowing for the calculation of left ventricular mass after correction for BSA; left ventricular mass and volumes were calculated by Schiller’s formula and Simpson’s rule by two-dimensional echocardiography (31).

Stroke volume and cardiac output were measured using pulsed Doppler echocardiography at the left ventricular outflow tract using two-dimensional echocardiography. Carotid sonography was performed with the subject in supine position with a slight rotation of the neck using a linear 3.0- to 11-mHz transducer. The probe was placed along the vessel axis to obtain a longitudinal scan of the common carotid arteries. Intima-media thickness was measured 1.5 cm proximal to the carotid artery bifurcation, and the mean of three measurements of each artery was reported in this study. Endothelium-dependent vasodilation was measured in the right brachial artery in each subject by the same observer. After 10 min of rest, brachial artery blood flow and the diameter of the brachial artery 2 cm above the antecubital fossa were determined using Doppler ultrasonography using a linear 3.0- to 11-mHz signal transducer. To induce hyperemia, a standard sphygmomanometer cuff was applied to the forearm just proximal to the wrist joint and inflated to 300 mm Hg for 5 min. Blood flow and brachial artery diameter measurements were repeated 45–60 sec after the release of sphygmomanometer pressure and were calculated as the percentage change in brachial diameter and percentage change in flow. Epicardial fat thickness was measured on the free wall of the right ventricle from both the parasternal long and short axis views. The maximum values at any site were measured and the average considered. The measurement of the epicardial fat on the right ventricle was chosen because it is recognized as the highest absolute epicardial fat layer thickness and because parasternal long- and short-axis views allow for the most accurate measurement of epicardial adipose tissue on the right ventricle.

Results are reported as mean ± SD. Between-group comparisons were made using ANOVA to analyze differences between patients and controls. Correlations were performed by linear regression analysis. Differences between patients were also analyzed in terms of their BMI, gender, and pubertal status. This study was performed with parental consent and with the approval of the hospitals’ ethics committee.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Cardiac mass and function

Left ventricular mass was 42.2 ± 2.4 g/m² in untreated GHD adolescents, 43.5 ± 6.3 g/m² in treated GHD subjects, and 49.9 ± 9.0 g/m² in controls. Left ventricular mass was significantly lower in untreated and treated GHD adolescents than controls (P < 0.05) (Table 2). Interventricular septum thickness and posterior wall thickness were, however, similar in treated and untreated GHD adolescents and controls (Table 2).

Carotid artery intima-media thickness and endothelium-dependent dilation of the brachial artery

Carotid artery intima-media thickness was similar in untreated and treated GHD adolescents and healthy controls (Table 2). Flow-mediated endothelium-dependent vasodilation of the brachial artery (percent change from baseline diameter during hyperemia) was 15.4 ± 1.1% in untreated GHD adolescents, 23.7 ± 3.1% in treated GHD patients, and 29.8 ± 2.1% in the controls. Flow-mediated endothelium-dependent vasodilation of the brachial artery was lower in untreated GHD patients than both controls and treated GHD subjects (P < 0.02) (Table 2). Hyperemia-induced blood flow increase (percent change from baseline) was greater in treated GHD adolescents than both untreated subjects and controls (253 ± 43% in treated GHD patients, 179 ± 69% in untreated subjects, and 144 ± 71% in controls; P < 0.001) (Table 2).

Epicardial adipose tissue

Echocardiographic epicardial adipose tissue was 2.76 ± 1.36 mm in untreated GHD subjects, 2.39 ± 0.51 mm in treated GHD adolescents, and 2.25 ± 0.75 mm in healthy controls. Epicardial adipose tissue was significantly higher in untreated GHD adolescents than treated GHD patients and healthy controls (P < 0.02).

Correlations

BMI correlated positively with epicardial adipose tissue in all three groups (P < 0.03, < 0.002, and < 0.01 and r = 0.84, 0.20, and 0.51, respectively, in controls, treated GHD adolescents, and untreated GHD patients). BMI also correlated positively with carotid intima-media thickness in treated and untreated GHD adolescents (P < 0.006 and < 0.002, r = 0.39 and 0.63) but did not correlate with the left ventricular mass in all three groups. When the data were analyzed after dividing treated and untreated patients and healthy controls according to gender and puberty, results were not different from those reported for the whole group.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In agreement with our previous study (26), carotid artery intima-media thickness was normal and similar to that of healthy controls in both treated and untreated GHD adolescents. The flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia was, however, lower in untreated GHD adolescents than in GHD-treated subjects or healthy controls, whereas the blood flow increase in the brachial artery after hyperemia was greater in treated GHD patients than untreated adolescents. Adult GHD has been found to be associated with endothelial dysfunction and an increased in large-artery stiffness (19). An improvement in endothelial function and a reduction in arterial stiffness has been reported after GH replacement, suggesting that the beneficial effect of GH treatment on cardiovascular function may be mediated in great part by the modulation of endothelial function (23, 24, 25). Endothelial function is impaired in GHD adults, and this involves the reduced availability of endothelial nitric oxide (NO), a vasodilatory compound; IGF-I has a direct NO-releasing effect on NO in cultured human endothelial cells and low basal IGF-I levels in serum are associated with low basal urinary nitrate and cAMP excretion (32). GH increases volemia and diminishes peripheral resistance in treated patients (33). It is of interest to note that the increase in hyperemia-induced blood flow was greater in treated GHD patients than normal controls in our study. One must, however, remember that we are reporting the percent of increase noted and not the absolute values seen in this group of patients; blood flow of the brachial artery was decreased in GHD patients in the basal state, and the percent change is therefore probably larger in this group once offered GH.

Increased levels of fasting and postprandial triglyceride-rich lipoproteins have been reported in untreated GHD adults and adolescents and seem to be related to an increase in the concentration of proinflammatory markers such as C-reactive protein, IL-6, and TNF, suggesting that lipoprotein remnants may induce an inflammatory response in endothelial cells and macrophages, which are secretors of cytokines (20, 22); an inverse correlation between low-density lipoprotein cholesterol and flow-mediated dilation has been reported in GHD adults. As demonstrated previously by Twickler et al. (20) in adults and by us in adolescents (22, 34), treatment with GH results in a decrease in the concentrations of postprandial triglyceride-rich lipoproteins and an improvement in flow-mediated dilation after GH has been shown by previous studies in adults (23, 24, 25) and this study in adolescents. From these studies it would seem that both biophysical and biochemical markers of endothelial function seem to be affected by GHD as early as in adolescence.

Echocardiographic epicardial adipose tissue measurement seems to be an easy and reliable imaging indicator of visceral adipose tissue and may prove to be a good marker for increased cardiovascular risk (27). Epicardial adipose tissue is a true visceral tissue deposited around the heart on the free wall of the right ventricle, on the left ventricular apex, and around the atria, and body fat distribution, particularly abdominal fat tissue, is strongly correlated to epicardial fat. A very good correlation with magnetic resonance imaging of both abdominal visceral adipose tissue and epicardial fat has been shown in adults and epicardial fat measurement has been related to both anthropometric and clinical parameters of the metabolic syndrome. In a recent study by Iacobellis et al. (27), epicardial adipose tissue was found to correlate with waist circumference, diastolic blood pressure, fasting plasma insulin, low-density lipoprotein cholesterol, and adiponectin levels in adults with the metabolic syndrome. Epicardial adipose tissue was found to be increased in our untreated GHD adolescents when compared with treated GHD subjects and healthy controls and to correlate positively with BMI, and this finding is in agreement with previous reports of increased fat mass with abdominal/visceral obesity in both children and adults with GHD (6, 7).

The decrease in the left ventricular mass of our untreated GHD adolescents is in agreement with the reports of Shulman et al. (16) and Salerno et al. (17), who recently found that GHD in children affects heart morphology by inducing a significant decrease in cardiac size. Although 1 yr of GH treatment normalized cardiac mass in those studies, we were unable to find any difference in cardiac mass between our treated and untreated GHD patients. Shulman et al. (16) and Salerno et al. (17) used somewhat higher GH doses to treat GHD subjects than did we, so that undertreatment of our GHD adolescents may have contributed to the lack of difference in left ventricular mass noted between treated and untreated GHD adolescents. Left ventricular performance, as manifested by a change in the ejection fraction, was similar in GHD subjects and healthy controls in both our study and that of Salerno et al.

GHD adolescents have a reduced left ventricular mass and vascular abnormalities manifested by lower flow-mediated endothelium-dependent vasodilation. These findings together with an increase in epicardial adipose tissue, a good indicator of abdominal/visceral fat demonstrate the presence of a number of potentially important differences between GHD patients and controls, which may contribute to an increased cardiovascular risk long term. An improvement in endothelial function and a reduction in arterial stiffness appear to occur after GH replacement.

	Acknowledgments

 
We thank Maria de la Luz Moraga (Representaciones Medicas Yoma, distributor for Philips of Venezuela) for making the transducer available to us.

	Footnotes

 
First Published Online May 3, 2005

Abbreviations: BMI, Body mass index; GHD, GH-deficient or GH deficiency; IGFBP, IGF binding protein; NO, nitric oxide; SDS, SD score.

Received January 18, 2005.

Accepted April 22, 2005.

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