- Email: [email protected]
Increased aortic stiffness in prepubertal girls with Turner syndrome
G Model
JJCC-1285; No. of Pages 7 Journal of Cardiology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Increased aortic stiffness in prepubertal girls with Turner syndrome Katya De Groote (MD)a,*, Daniel Devos (MD)b, Koen Van Herck (MD, PhD)c,d, Daniel De Wolf (MD, PhD)d, Saskia Van der Straaten (MD)e, Ernst Rietzschel (MD, PhD)f, Ann Raes (MD, PhD)g, Kristof Vandekerckhove (MD)d, Joseph Panzer (MD)d, Hans De Wilde (MD)d, Jean De Schepper (MD, PhD)h a
Pediatric Cardiology, Department of Pediatrics and Turner Clinic, Ghent University Hospital, Ghent, Belgium Cardiovascular Radiology, Department of Radiology and Turner Clinic, Ghent University Hospital, Ghent, Belgium Department of Public Health, Ghent University, Ghent, Belgium d Pediatric Cardiology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium e Pediatric Endocrinology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium f Department of Cardiology, Ghent University Hospital and Ghent University, Ghent University Hospital, Ghent, Belgium g Pediatric Nephrology, Department of Pediatrics and Safepedrug, Ghent University Hospital, Ghent, Belgium h Pediatric Endocrinology, Department of Pediatrics and Turner Clinic, Ghent University Hospital, Ghent, Belgium b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 January 2016 Received in revised form 24 February 2016 Accepted 1 March 2016 Available online xxx
Background: Aortic dilation and dissection contribute highly to the increased mortality of Turner syndrome (TS) but the exact pathophysiology is not completely understood. Design: Prospective case – control study. Methods: 15 prepubertal TS girls (median age 10.64, IQ 8.31–11.04) with a tricuspid (TAV, n = 9) or a bicuspid (BAV, n = 6) aortic valve, and 31 sex-, age-, and height-matched healthy controls underwent a cardiac and vascular ultrasound to evaluate aortic dimensions and elastic properties of the aortic wall. Results: TS BAV had significantly larger ascending aortic diameters than controls for absolute diameter, 22.2 5.1 mm vs. 18.6 1.9 mm (p = 0.014) and z-score 1.7 2.1 vs. 0.1 0.7 (p = 0.008). Distensibility of the ascending aorta was lower in the TS than in controls (40.2 103 kPa1, IQ 31.3–56.2 vs. 62.9 103 kPa1, IQ 55.5–76.5, p = 0.003), both for TS TAV (p = 0.014) and BAV (p = 0.005). Stiffness index was higher in TS than in controls (5.26, IQ 3.34–5.26 vs. 3.23, IQ 2.55–3.24, p = 0.005), both for TS TAV (p = 0.028) and TS BAV (p = 0.006). Pulse wave velocity was not different between groups. There was no correlation between stiffness and z-score of the ascending aortic diameter. Conclusions: In prepubertal TS girls, stiffness of the ascending aorta is increased in patients with a BAV and TAV while dilation of the ascending aorta is more frequent in BAV. This suggests an intrinsic aortic wall abnormality making all TS patients at increased risk for severe aortic complications although the risk is the highest for TS with BAV. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Aortic dilation Aortic rupture Aortic elastic properties Childhood Echocardiography
Introduction Turner syndrome (TS) is a chromosomal disorder, occurring in approximately 1 per 2000 live born girls [1] and is typically associated with reduced final height and gonadal failure. Cardiovascular pathology is highly prevalent in TS patients, contributing to the high morbidity and mortality of the syndrome [2]. Structural
* Corresponding author at: Ghent University Hospital, Pediatric Cardiology, 3K12D, De Pintelaan 185, 9000 Ghent, Belgium. Tel.: +32 9 332 24 60; fax: +32 39 332 38 56. E-mail address: [email protected] (K. De Groote).
congenital heart defects are present in 25–50% of TS patients; bicuspid aortic valve and coarctation of the aorta are the most common [3–6]. Additionally, progressive dilation of the ascending aorta is observed in 20–25% of TS patients. Although the prevalence appears to increase with age, abnormal aortic dimensions are present from childhood [7,8]. Hypertension, which affects onefourth of the children [9] and up to half of the adults with TS [10], coarctation of the aorta, and bicuspid aortic valve are all associated with aortic dilation and dissection. However, dilation and dissection also occur in patients without those risk factors [11–13]. Aortic dilation was found to be inversely correlated with aortic distensibility in a group of TS patients of varying age and an intrinsic abnormal elasticity of the aortic wall has been suggested
http://dx.doi.org/10.1016/j.jjcc.2016.03.006 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 2
K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
as a predictive risk factor for aortic dilatation in TS [14]. In a group of TS patients aged 9–20 years, vasculopathy was observed as compared to obese and lean controls [15]. Since the abnormal aortic dimensions in TS might be the result of a generalized vasculopathy starting from childhood, we examined if abnormal rigidity of the aorta is present from a young age and if it is associated with an increased carotid artery diameter or intima-media thickness. Therefore, the distensibility and stiffness of the ascending aorta and the whole aortic arch were investigated in young prepubertal TS girls, compared to normal controls matched for sex, age, and height. Methods Study population Patients were recruited in the Pediatric Department of Ghent University Hospital, Belgium. Girls with TS confirmed on karyotype were eligible for the study if they were older than 6 years (to have full cooperation) and prior to puberty induction or spontaneous puberty (to avoid the effect of estrogen). The control group consisted of healthy girls without any medical history, who were matched for age and height. The study protocol was approved by the ethical committee of Ghent University Hospital. All girls and their parents gave written informed consent. All examinations were performed during a single visit to the pediatric cardiology department of Ghent University Hospital by a single experienced pediatric cardiologist (KDG).
Echocardiography Echocardiography was performed with the patient in a supine position and with the use of a VIVID 7 ultrasound (GE Vingmed Ultrasound, Horten, Norway) equipped with a 3.5 MHz probe. Data were stored and used for offline analysis by one single observer (KDG) using EchoPAC version 110.1.0 software (GE Vingmed Ultrasound). All patients and controls underwent a complete ultrasound evaluation of the heart to exclude previously unknown pathology such as abnormal aortic valve morphology or aortic coarctation. For each parameter, measurements were performed on at least 3 cardiac cycles and averaged. Diameters of the aorta were measured from the parasternal long axis at the level of the aortic valve annulus, aortic root and ascending aorta at the level of the right pulmonary artery. The interventricular septum, posterior wall and internal diameters were measured on a parasternal short axis and used for calculation of fractional shortening and Devereux index. For each variable, z-scores were calculated according to the Sluysmans data [19]. For the aortic root and ascending aorta, zscore was calculated using our own previously reported Campens formula [20]. On the parasternal long axis, an M-mode image of the ascending aorta was recorded. Care was taken to place the aorta horizontally on the screen with the cursor perpendicular to the arterial wall at the level of the right pulmonary artery. On the Mmode recording, the diameter of the ascending aorta was measured from inner to inner surface during diastole and systole (Fig. 1). The mean of 10 M-mode measurements and the mean of 3 blood pressure measurements performed during the ultrasound exam were used for calculation of the aortic stiffness index and distensibility as described below [21]
Anthropometry Body height was measured with a wall mounted stadiometer and body weight with an electronic scale. Height, weight, and body mass index (BMI) z-scores were calculated using Flemish reference growth data, and body surface area (BSA) according to Haycock’s formula [16].
2 6 Distensibility 6 4diameter 2
diast
2
h i blood pressure ln blood pressure syst diast i ðdimensionlessÞ Aortic stiffness index h diametersyst diameterdiast diameterdiast
and
diametersyst 2 2
p
diameterdiast 2
2
p
3
7 7107 ðin 103 kPa1 Þ 5 p ðblood pressuresyst blood pressurediast Þ1333
Blood pressure Blood pressure was taken at the 4 limbs, with the patient at rest and in a supine position (Accutorr Plus, Datascope, Mahwah, NJ, USA with an appropriate pediatric cuff). Additionally, blood pressure was taken 3 times at the right arm during the ultrasound examination. The mean of these 3 measurements was used for statistics and the calculation of distensibility and stiffness index. In-office blood pressure was considered normal if below the 95th percentile for sex, age, and height [17]. For Turner girls, an additional 24-h blood pressure registration was performed (Tonoport V, Par Medzintechnik, Berlin, Germany) and analyzed using the normal values for sex and age described by Wuhl et al. [18]. Abnormal nocturnal dipping was defined as:
systolic blood pressure during night time 100 < 10% 1 systolic blood pressure during day time
Fig. 1. M-mode recording of the ascending aorta on the parasternal long axis. The diameter of the ascending aorta is measured in diastole and systole.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
Vascular examination
Results
The patient was positioned with the head rotated 458 to the left. Using a vascular transducer 12L set at 10 MHz, the right carotid artery was visualized at the site of the bifurcation. The intimamedia thickness (IMT) of the far wall of the common carotid artery was measured 10 mm below the bifurcation at the end of diastole, using the automatic border detection of the EchoPAC system. The inner diameter of the carotid artery was measured at the end of diastole [22]. The mean of at least 10 measurements was used for analysis. Pulse wave (PW) Doppler signals were obtained consecutively at the right common carotid artery and the right femoral artery. The time interval (Dtime) between the arrival of the pulse at the carotid and femoral arteries was calculated using the foot-to-foot velocity method as described earlier (Fig. 2) [23]. The distance (D) was calculated as the distancecarotid arteryfemoral artery distancecarotid artery-suprasternal notch. PW velocity (V) was then defined as D/Dtime expressed in m/s. The mean of 15 Doppler measurements was used for analysis.
Study population
3
All 15 eligible TS girls agreed to participate and were enrolled in the study. Their karyotypes were 45,X (n = 6), 45,X/46,XX (n = 2), 45,X/46,XX/47,XX (n = 3), and others (n = 4). Two girls had a history of aortic coarctation that was treated surgically in the neonatal period with a good functional result. Twelve TS girls were treated with growth hormone at the time of the study (mean duration 3.4 years, range 0.5–6.5 years); none received any other medication. The control group consisted of 32 healthy prepubertal girls who were matched for age and height. One control showed a normally functioning but bicuspid aortic valve with marked dilation of the ascending aorta and was excluded from the analysis. With 15 TS patients and 31 controls, post hoc power analysis yielded a power of 94%. Data on age, body height, weight, and BMI are presented in Table 1. TS patients and controls did not differ in age and height but BMI and body weight z-score were statistically lower in the control than in the TS group.
Statistical analysis Blood pressure Statistical analysis was performed using SPSS, Statistics 23 (IBM, Chicago, IL, USA). If data were normally distributed, they were presented as mean SD and analyzed by parametric tests (unpaired t-test and ANOVA with Bonferroni post hoc analysis). If data were not normally distributed, they were presented as median (interquartile ranges) and analyzed using non-parametric tests (Kruskal–Wallis, Mann–Whitney U, and median K samples). Differences were considered statistically significant if p < 0.05.
In-office blood pressure was normal in all girls and there was no statistically significant difference between the TS patients and the controls (Table 2). All participants had higher blood pressures in the lower than in the upper limbs. Ambulatory 24-hour blood pressure values were available for 11 TS patients: 3 measurements were declined by the patient and 1 registration failed due to technical reasons. In 4 TS patients (33%), ambulatory blood pressure measurement revealed hypertension during the daytime but the mean systolic and diastolic blood pressures exceeded the normal values only mildly. Non-dipping was found in 5 patients (45%). Aortic valve morphology Aortic valve morphology (bicuspid or tricuspid) could be appreciated satisfactorily in all cases. In the TS group, 6 patients (40%) had a bicuspid aortic valve (BAV). None of the valves were stenotic or insufficient. All 31 controls had a normally functioning tricuspid aortic valve (TAV). Diameters of the aorta The ascending aorta diameters in the TS group were significantly higher than in the control group (p = 0.012). When TS girls with BAV and TAV were analyzed separately, there was only a statistically significant difference in ascending aorta size between TS patients with a BAV and the controls, both for absolute diameters (p = 0.014) and the calculated z-scores (p = 0.008)
Table 1 Biometry of the Turner syndrome and the control group.
Age (y) Weight (kg) Height (cm) BMI (kg/m2) Weight z-score Height z-score BMI z-score Fig. 2. Pulse wave (PW) Doppler signal at the femoral artery (upper part) and the common carotid artery (lower part). For both signals, the time interval is measured between the onset of the QRS complex and the onset of the systolic PW Doppler signal. Dtime is calculated as the difference between both time intervals.
Turner patients (N = 15)
Controls (N = 31)
p-value
10.6 (8.3 to 11.0) 31.2 (25.4 to 40.2) 133.4 (125.6 to 138.1) 17.53 (16.07 to 19.23) S0.8 (S1.0 to 0.3) S1.6 (S2.1 to S0.8) 0.2 (0.0 to 0.8)
10.4 (7.7 to 11.7) 27.0 (23.4 to 31.1) 130.8 (125.3 to 140.5) 15.53 (14.65 to 16.53) S1.0 (S1.9 to S0.7) S1.40 (S2.0 to S0.2) S0.6 (S1.4 to S0.2)
0.963 0.085 0.907 <0.001 0.022 0.656 <0.001
Data presented as median (interquartile ranges) or mean SD. BMI, body mass index. p-values shown in bold are considered statistically significant.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
4
Table 2 Cardiovascular data of controls versus TS patients with a TAV and a BAV.
SBP (mmHg) DBP (mmHg) AoAsc (mm) AoAsc z-score AoRoot (mm) AoRoot z-score Carotid diameter (mm) cIMT (mm) Stiffness index Distensibility (103 kPa1) PWV (m/s) Devereux index (g/m2)
Controls (N = 30)
TS TAV (N = 9)
TS BAV (N = 6)
p-value overall
p-value C–TS TAV
p-value C–TS BAV
p-value TS TAV–TS BAV
101.21 7.91 63.5 6.09 18.62 1.88 0.14 0.69 19.03 (17.88–21.72) 0.78 0.88 4.68 (4.48–4.87) 0.48 (0.46–0.51) 3.22 (2.53–3.56) 63.18 (55.52–76.96) 3.82 (3.54–4.29) 60.24 (54.49–69.18)
103.26 8.57 66.82 7.37 20.17 2.47 0.57 1.17 20.26 (19.13–21.55) 0.40 1.19 5.03 (4.48–5.33) 0.47 (0.44–0.52) 3.92 (2.98–5.99) 49.19 (33.95–66.52) 4.01 (3.77–4.48) 74.32 (60.28–77.02)
101.94 7.80 65.67 7.70 22.16 5.10 1.66 2.05 21.12 (18.79–24.97) 0.15 1.45 5.03 (4.45–5.56) 0.47 (0.45–0.52) 5.60 (4.53–6.68) 33.37 (29.41–51.05) 3.87 (3.57–4.17) 71.33 (53.13–96.81)
0.797 0.375 0.012 0.010 0.139 0.118 0.279 0.161 0.005 0.003 0.414 0.061
1.000 0.572 0.392 0.913 0.490 0.990 0.164 0.048 0.028 0.014 0.230 0.028
1.000 1.000 0.014 0.008 0.286 0.144 0.180 0.865 0.006 0.005 0.445 0.203
1 1 0.474 0.170 1 0.945 1 0.556 0.346 0.289 0.239 0.841
One distinct outlier in the control group, the older sister of the excluded control with a bicuspid valve, probably suffers from a congenital familial aortic disease and was excluded from further analysis of the aortic stiffness. Her data are not included in this table. Data presented as median (interquartile ranges) or mean SD. C, controls; TS TAV, Turner syndrome patients with a tricuspid aortic valve; TS BAV, Turner syndrome patients with a bicuspid aortic valve; SBP, systolic blood pressure; DBP, diastolic blood pressure (mean of 3 measurements during the ultrasound exam); AoAsc, ascending aorta diameter; AoRoot, aortic root diameter; cIMT, intima-media thickness of the common carotid artery; PWV, pulse wave velocity. p-values shown in bold are considered statistically significant.
(Fig. 3 and Table 2). The other aortic diameters were not statistically different between the TS and the control groups (Table 2). Distensibility and stiffness of the aortic arch The ascending aorta of TS girls showed a significantly higher stiffness index (p = 0.005) and lower distensibility (p = 0.003) than the controls (Table 2). In the control group, there was 1 distinct outlier
with a severely decreased distensibility and increased stiffness index, the older sister of the excluded control with a bicuspid valve. This girl probably suffers from a congenital familial aortic disease and was excluded from further analysis of the aortic stiffness. When TS girls with BAV and TAV were analyzed separately, a distinct difference in ascending aorta stiffness index and distensibility remained between controls and TS girls, both with BAV or TAV (Table 2 and Fig. 4).
Fig. 3. Absolute (mm, panel A) and relative (z-score, panel B) ascending aorta diameters for the 3 groups. Turner syndrome (TS) with TAV: patients with TS and a tricuspid aortic valve. TS with BAV: patients with TS and a bicuspid aortic valve.
Fig. 4. Stiffness index (panel A), distensibility (panel B), and PWV (panel C) in the control group versus the TS group with TAV and BAV. PWV, pulsed wave velocity; TS, Turner syndrome; TAV, tricuspid aortic valve; BAV, bicuspid aortic valve.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
Pulse wave velocity between the carotid and femoral arteries did not show any significant difference between groups (Table 2 and Fig. 4). Two TS girls, one with a BAV and one with a TAV, were previously surgically treated for coarctation. To exclude the impact of coarctation on the elasticity parameters, we repeated the analysis without those 2 girls. The statistically significant difference between TS patients and controls remained for stiffness index (p = 0.022) and distensibility (p = 0.012). Carotid artery There was neither statistically significant difference in carotid artery diameter nor in IMT between the Turner and the control group (Table 2). Cardiac function There was no statistically significant difference in parameters of systolic or diastolic function between the groups. Only the cardiac mass, expressed as the Devereux index, was slightly higher in the TS TAV group compared to controls (Table 2). Discussion This is the first report on aortic distensibility and stiffness in a non-selected group of young prepubertal TS girls. Our data show an increased stiffness and decreased distensibility of the ascending aorta of young TS girls with a BAV and TAV whereas severe aortic dilation was restricted to TS girls with a BAV. This suggests that TS girls have an aortic wall abnormality that is inherent to the genetic problem and that, although progressive with age, aortic dilation should be considered a congenital cardiovascular defect. Although the literature contains a large amount of data on aortic pathology in TS, the interpretation of most studies is complicated by non-homogenous study populations, the presence of comorbidity, and the intake of multiple drugs. In addition, the physiological influence of age on the aortic wall and the possible impact of estrogen deficiency and hormone replacement therapy on aortic wall properties are not always taken into account. This study was conducted to overcome at least some of these interfering factors. All TS girls were prepubertal to minimize the possible effect of estrogen deficiency in the development of aortic dilation. In this young age group, there was no co-morbidity of diabetes, thyroid dysfunction, metabolic syndrome, or severe hypertension and there was no interference of medical therapy other than growth hormone. In our study group, the youngest studied to date, we found significantly larger diameters in the TS group at the site of the ascending aorta. However, when the aortic valve morphology was taken into account, dimensions were only significantly larger in those with a BAV. Enlarged aortic dimensions in pediatric TS patients were reported previously [7,8]. Lopez et al. described that a BAV is a risk factor for aortic dilation in childhood. In contrast to our findings, they also found larger aortas in TS patients with a normal aortic valve, but unlike ours, their study population contained both pubertal and prepubertal girls [8]. In our prepubertal girls, either with a BAV or a TAV, the ascending aorta was significantly stiffer than those of the healthy controls. Pulse wave velocity between the right carotid and right femoral artery was not different between TS and controls, suggesting a similar elasticity along the total length of the aorta and a selective disease of the proximal part of the aorta, independent of aortic valve morphology. This finding is in line with the results of post mortem studies in TS women after aortic rupture that describe type A dissections in 2/3 of the cases
5
[11,24]. An alternative explanation for the discrepancy between the M-mode and the PWV results could be found in the method of the ultrasound PWV measurement. The distance traveled by the pulse is measured with a tape measure from the carotid to the femoral measuring site. This however presumes a normal aortic arch morphology without elongation or abnormal kinking. As adult TS patients often have an abnormal arch morphology [5,25,26], the tape measure is possibly not representative for the aortic length and underestimates the real distance traveled by the pulse. In our study population, 6 TS girls (40%) had a BAV compared to the 12–39% described in the literature [3,6,8,27–30]. In the general population, BAV are associated with dilation of the aortic root and the ascending aorta that can lead to aortic dissection and rupture. They are also associated with impaired aortic elasticity, independently of the presence of aortic dilation [31,32]. The abnormal elasticity of the ascending aorta in our young TS patients however was not restricted to TS patients with a BAV. This suggests that the abnormal aortic wall property in TS is a primary defect and not secondary to the presence of a BAV. This finding is in line with data in adults describing rapid aortic growth and aortic rupture in TS women with a normal TAV [33]. Although not statistically significant, elasticity in TS patients with a BAV was more impaired than in those with a TAV, suggesting an additive effect of BAV and an intrinsic wall abnormality. Coarctation is reported in 4–15% of TS patients [3,5,27,28,30] and is known to cause aortic dilation, abnormal arch morphology, and increased proximal aortic stiffness [34–36]. Our TS group contained 2 girls with a coarctation that was treated in the neonatal period. To examine a possible bias due to the coarctation, analysis was repeated after exclusion of these two patients, but this did not influence the results. In-office blood pressure measurements were normal in all participants and there was no difference in systolic or diastolic blood pressure between the study and the control groups. However, on 24-h blood pressure measurement, hypertension was found in 4 girls and abnormal nocturnal dipping in 5. The number of patients was insufficient to examine the influence of 24h blood pressure on aortic diameters or elasticity. Vascular pathology in TS is not limited to the aorta. Ostberg et al. also showed an increased diameter of the carotid artery and a thicker intima-media thickness in adult TS women compared to normal controls [37]. In a younger TS population, the increase in IMT was not observed [15,38]. Our study could not find a difference in IMT or carotid diameter between young TS girls and matched controls. This probably can be explained by the young age of our TS study group and cannot rule out possible progression in the future. The major limitations of this study are the small number of patients included, the possible interference with growth hormone, and the lower body weight of the control group. TS is frequently diagnosed during adolescence, making it difficult to recruit prepubertal patients. In our study group of 15 patients, the diagnosis of TS was made at a young age with a prenatal diagnosis in 5 of them. We cannot rule out that this caused a selection bias toward the more severe TS phenotypes. Twelve TS girls (80%) received standard doses of growth hormone. Due to ethical considerations, it was impossible to stop this treatment for a long period. There are however little indications that growth hormone has a detrimental influence on aortic elasticity or aortic dimensions. In a prospective study, Lawson et al. could not find an association between vasculopathy and growth hormone treatment in TS girls [15]. Bondy et al. did not find a difference in heightcorrected aortic diameters in TS who received (or had received) growth hormone compared to those who did not receive (or had not received) growth hormone [39]. Van den Berg et al. found an impaired aortic elasticity in adult TS patients but those who received high doses of growth hormone during childhood and
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
6
adolescents showed an elasticity that was comparable to the normal [40]. The results presented here indicate an increased stiffness of the ascending aorta from early age on, both in TS patients with a TAV and BAV, and earlier ascending aorta dilation in those with a BAV. These data support the idea that all TS patients are at increased risk for severe aortic complications, but that the risk of those with a BAV is the highest. Follow-up studies are needed to see if young patients with increased aortic stiffness but currently normal diameters evolve toward dilation at an older age. Secondly, the question remains if increased stiffness leads to a higher risk for dissection and rupture even in the absence of severe dilation. Probably other TS-related factors such as hypertension, dyslipidemia, diabetes, or pregnancy play an additional role. Conclusions In prepubertal TS girls, the stiffness of the ascending aorta is increased in patients with a BAV and a TAV while dilation of the ascending aorta is more frequent in those with a BAV. These data suggest an intrinsic abnormal aortic wall property in TS patients making them all at risk for severe aortic complications although the risk is the highest for those with a BAV. If increased stiffness plays an important role in the evolution toward dissection, it might be useful to include measurement of distensibility and stiffness in the risk assessment of TS patients. Large prospective studies however are needed to support this hypothesis. Funding Daniel Devos is recipient of a KOF clinical fellowship nr AB/SDS/ 799/2008/hdp from the University Hospital Ghent. Danilo Babin is recipient of IWT (Spin-off) Innovation Mandate 130865. Disclosure statement None of the authors have relationships with industry to disclose, nor any conflict of interest relevant to the contents of this paper. Author contributions Each of us acknowledges that he or she participated sufficiently in the work to take public responsibility for its content References [1] Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. [2] Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA. Mortality in women with turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab 2008;93:4735–42. [3] Gotzsche CO, Krag-Olsen B, Nielsen J, Sorensen KE, Kristensen BO. Prevalence of cardiovascular malformations and association with karyotypes in Turner’s syndrome. Arch Dis Child 1994;71:433–6. [4] Gravholt CH. Clinical practice in Turner syndrome. Nat Clin Pract Endocrinol Metab 2005;1:41–52. [5] Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, Bondy CA. Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features. Circulation 2004;110:1694–700. [6] Mazzanti L, Prandstraller D, Fattori R, Lovato L, Cicognani A, Italian Study Group for Turner Syndrome. Monitoring of congenital heart disease (CHD) and aortic dilatation in Turner syndrome: Italian experience. Int Congr Series 2006;1298:123–30. [7] Chalard F, Ferey S, Teinturier C, Kalifa G. Aortic dilatation in Turner syndrome: the role of MRI in early recognition. Pediatr Radiol 2005;35:323–6.
[8] Lopez L, Arheart KL, Colan SD, Stein NS, Lopez-Mitnik G, Lin AE, Reller MD, Ventura R, Silberbach M. Turner syndrome is an independent risk factor for aortic dilation in the young. Pediatrics 2008;121:e1622–27. [9] Nathwani NC, Unwin R, Brook CG, Hindmarsh PC. Blood pressure and Turner syndrome. Clin Endocrinol (Oxf) 2000;52:363–70. [10] De Groote K, Demulier L, De Backer J, De Wolf D, De Schepper J, T’sjoen G, De Backer T. Arterial hypertension in Turner syndrome: a review of the literature and a practical approach for diagnosis and treatment. J Hypertens 2015;33: 1342–51. [11] Carlson M, Airhart N, Lopez L, Silberbach M. Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the international turner syndrome aortic dissection registry. Circulation 2012;126:2220–6. [12] Gravholt CH, Landin-Wilhelmsen K, Stochholm K, Hjerrild BE, Ledet T, Djurhuus CB, Sylve´n L, Baandrup U, Kristensen BØ, Christiansen JS. Clinical and epidemiological description of aortic dissection in Turner’s syndrome. Cardiol Young 2006;16:430–6. [13] Mortensen KH, Hjerrild BE, Stochholm K, Andersen NH, Sorensen KE, Lundorf E, Hørlyck A, Pedersen EM, Christiansen JS, Gravholt CH. Dilation of the ascending aorta in Turner syndrome – a prospective cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2011;13:24. [14] Sharma J, Friedman D, Dave-Sharma S, Harbison M. Aortic distensibility and dilation in Turner’s syndrome. Cardiol Young 2009;19:568–72. [15] Lawson SA, Urbina EM, Gutmark-Little I, Khoury PR, Gao Z, Backeljauw PF. Vasculopathy in the young Turner syndrome population. J Clin Endocrinol Metab 2014;99:E2039–45. [16] Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr 1978;93:62–6. [17] National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114(2 Suppl. 4th Report):555–76. [18] Wuhl E, Witte K, Soergel M, Mehls O, Schaefer F. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens 2002;20:1995–2007. [19] Sluysmans T, Colan SD. Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 2005;99:445–57. [20] Campens L, Demulier L, De Groote K, Vandekerckhove K, De Wolf D, Roman MJ, Devereux RB, De Paepe A, De Backer J. Reference values for echocardiographic assessment of the diameter of the aortic root and ascending aorta spanning all age categories. Am J Cardiol 2014;114:914–20. [21] Hauser M, Kuhn A, Petzuch K, Wolf P, Vogt M. Elastic properties of the ascending aorta in healthy children and adolescents. Age-related reference values for aortic wall stiffness and distensibility obtained on M-mode echocardiography. Circ J 2013;77:3007–14. [22] Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, Jacobson M, Mahoney L, Mietus-Snyder M, Rocchini A, Steinberger J, McCrindle B, American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension 2009;54:919–50. [23] Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H, European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006;27:2588–605. [24] Bondy CA. Aortic dissection in Turner syndrome. Curr Opin Cardiol 2008;23: 519–26. [25] De Groote K, Devos D, Van Herck K, Demulier L, Buysse W, De Schepper J, De Wolf D. Abnormal aortic arch morphology in Turner syndrome patients is a risk factor for hypertension. Heart Vessels 2015;30:618–25. [26] Mortensen KH, Hjerrild BE, Andersen NH, Sorensen KE, Horlyck A, Pedersen EM, Lundorf E, Christiansen JS, Gravholt CH. Abnormalities of the major intrathoracic arteries in Turner syndrome as revealed by magnetic resonance imaging. Cardiol Young 2010;20:191–200. [27] Douchin S, Rossignol AM, Klein SK, Siche JP, Baguet JP, Bost M. Heart malformations and vascular complications associated with Turner’s syndrome. Prospective study of 26 patients. Arch Mal Coeur Vaiss 2000;93: 565–70. [28] Prandstraller D, Mazzanti L, Picchio FM, Magnani C, Bergamaschi R, Perri A, Tsingos E, Cacciari E. Turner’s syndrome: cardiologic profile according to the different chromosomal patterns and long-term clinical follow-up of 136 nonpreselected patients. Pediatr Cardiol 1999;20:108–12. [29] Sybert VP. Cardiovascular malformations and complications in Turner syndrome. Pediatrics 1998;101:E11. [30] Kim HK, Gottliebson W, Hor K, Backeljauw P, Gutmark-Little I, Salisbury SR, Racadio JM, Helton-Skally K, Fleck R. Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population. Am J Roentgenol 2011;196: 454–60. [31] Moaref A, Khavanin M, Shekarforoush S. Aortic distensibility in bicuspid aortic valve patients with normal aortic diameter. Ther Adv Cardiovasc Dis 2014;8: 128–32.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx [32] Oulego-Erroz I, Alonso-Quintela P, Mora-Matilla M, Gautreaux Minaya S, ˜ a-Lo´pez de Armentia S. Ascending aorta elasticity in children with Lapen isolated bicuspid aortic valve. Int J Cardiol 2013;168:1143–6. [33] Carlson M, Silberbach M. Dissection of the aorta in Turner syndrome: two cases and review of 85 cases in the literature. J Med Genet 2007;44:745–9. [34] Ou P, Bonnet D, Auriacombe L, Pedroni E, Balleux F, Sidi D, Mousseaux E. Late systemic hypertension and aortic arch geometry after successful repair of coarctation of the aorta. Eur Heart J 2004;25:1853–9. [35] Ou P, Mousseaux E, Celermajer DS, Pedroni E, Vouhe P, Sidi D, Bonnet D. Aortic arch shape deformation after coarctation surgery: effect on blood pressure response. J Thorac Cardiovasc Surg 2006;132:1105–11. [36] Ou P, Celermajer DS, Raisky O, Jolivet O, Buyens F, Herment A, Sidi D, Bonnet D, Mousseaux E. Angular (Gothic) aortic arch leads to enhanced systolic wave reflection, central aortic stiffness, and increased left ventricular mass late after
[37]
[38]
[39] [40]
7
aortic coarctation repair: evaluation with magnetic resonance flow mapping. J Thorac Cardiovasc Surg 2008;135:62–8. Ostberg JE, Donald AE, Halcox JP, Storry C, McCarthy C, Conway GS. Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction. J Clin Endocrinol Metab 2005;90:5161–6. Radetti G, Mazzanti L, Di Somma C, Salerno M, Gottardi E, Capalbo D, Tamburrino F, Colao A. Evaluation of function and structure of arterial wall in girls and young women with Turner syndrome. J Endocrinol Invest 2015;38:963–70. Bondy CA, Van PL, Bakalov VK, Ho VB. Growth hormone treatment and aortic dimensions in Turner syndrome. J Clin Endocrinol Metab 2006;91:1785–8. van den Berg J, Bannink E, Wielopolski P, Pattynama PM, de Muinck KeizerSchrama SM, Helbing W. Aortic distensibility and dimensions and the effects of growth hormone treatment in the turner syndrome. Am J Cardiol 2006;97:1644–9.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
JJCC-1285; No. of Pages 7 Journal of Cardiology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Increased aortic stiffness in prepubertal girls with Turner syndrome Katya De Groote (MD)a,*, Daniel Devos (MD)b, Koen Van Herck (MD, PhD)c,d, Daniel De Wolf (MD, PhD)d, Saskia Van der Straaten (MD)e, Ernst Rietzschel (MD, PhD)f, Ann Raes (MD, PhD)g, Kristof Vandekerckhove (MD)d, Joseph Panzer (MD)d, Hans De Wilde (MD)d, Jean De Schepper (MD, PhD)h a
Pediatric Cardiology, Department of Pediatrics and Turner Clinic, Ghent University Hospital, Ghent, Belgium Cardiovascular Radiology, Department of Radiology and Turner Clinic, Ghent University Hospital, Ghent, Belgium Department of Public Health, Ghent University, Ghent, Belgium d Pediatric Cardiology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium e Pediatric Endocrinology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium f Department of Cardiology, Ghent University Hospital and Ghent University, Ghent University Hospital, Ghent, Belgium g Pediatric Nephrology, Department of Pediatrics and Safepedrug, Ghent University Hospital, Ghent, Belgium h Pediatric Endocrinology, Department of Pediatrics and Turner Clinic, Ghent University Hospital, Ghent, Belgium b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 January 2016 Received in revised form 24 February 2016 Accepted 1 March 2016 Available online xxx
Background: Aortic dilation and dissection contribute highly to the increased mortality of Turner syndrome (TS) but the exact pathophysiology is not completely understood. Design: Prospective case – control study. Methods: 15 prepubertal TS girls (median age 10.64, IQ 8.31–11.04) with a tricuspid (TAV, n = 9) or a bicuspid (BAV, n = 6) aortic valve, and 31 sex-, age-, and height-matched healthy controls underwent a cardiac and vascular ultrasound to evaluate aortic dimensions and elastic properties of the aortic wall. Results: TS BAV had significantly larger ascending aortic diameters than controls for absolute diameter, 22.2 5.1 mm vs. 18.6 1.9 mm (p = 0.014) and z-score 1.7 2.1 vs. 0.1 0.7 (p = 0.008). Distensibility of the ascending aorta was lower in the TS than in controls (40.2 103 kPa1, IQ 31.3–56.2 vs. 62.9 103 kPa1, IQ 55.5–76.5, p = 0.003), both for TS TAV (p = 0.014) and BAV (p = 0.005). Stiffness index was higher in TS than in controls (5.26, IQ 3.34–5.26 vs. 3.23, IQ 2.55–3.24, p = 0.005), both for TS TAV (p = 0.028) and TS BAV (p = 0.006). Pulse wave velocity was not different between groups. There was no correlation between stiffness and z-score of the ascending aortic diameter. Conclusions: In prepubertal TS girls, stiffness of the ascending aorta is increased in patients with a BAV and TAV while dilation of the ascending aorta is more frequent in BAV. This suggests an intrinsic aortic wall abnormality making all TS patients at increased risk for severe aortic complications although the risk is the highest for TS with BAV. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Aortic dilation Aortic rupture Aortic elastic properties Childhood Echocardiography
Introduction Turner syndrome (TS) is a chromosomal disorder, occurring in approximately 1 per 2000 live born girls [1] and is typically associated with reduced final height and gonadal failure. Cardiovascular pathology is highly prevalent in TS patients, contributing to the high morbidity and mortality of the syndrome [2]. Structural
* Corresponding author at: Ghent University Hospital, Pediatric Cardiology, 3K12D, De Pintelaan 185, 9000 Ghent, Belgium. Tel.: +32 9 332 24 60; fax: +32 39 332 38 56. E-mail address: [email protected] (K. De Groote).
congenital heart defects are present in 25–50% of TS patients; bicuspid aortic valve and coarctation of the aorta are the most common [3–6]. Additionally, progressive dilation of the ascending aorta is observed in 20–25% of TS patients. Although the prevalence appears to increase with age, abnormal aortic dimensions are present from childhood [7,8]. Hypertension, which affects onefourth of the children [9] and up to half of the adults with TS [10], coarctation of the aorta, and bicuspid aortic valve are all associated with aortic dilation and dissection. However, dilation and dissection also occur in patients without those risk factors [11–13]. Aortic dilation was found to be inversely correlated with aortic distensibility in a group of TS patients of varying age and an intrinsic abnormal elasticity of the aortic wall has been suggested
http://dx.doi.org/10.1016/j.jjcc.2016.03.006 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 2
K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
as a predictive risk factor for aortic dilatation in TS [14]. In a group of TS patients aged 9–20 years, vasculopathy was observed as compared to obese and lean controls [15]. Since the abnormal aortic dimensions in TS might be the result of a generalized vasculopathy starting from childhood, we examined if abnormal rigidity of the aorta is present from a young age and if it is associated with an increased carotid artery diameter or intima-media thickness. Therefore, the distensibility and stiffness of the ascending aorta and the whole aortic arch were investigated in young prepubertal TS girls, compared to normal controls matched for sex, age, and height. Methods Study population Patients were recruited in the Pediatric Department of Ghent University Hospital, Belgium. Girls with TS confirmed on karyotype were eligible for the study if they were older than 6 years (to have full cooperation) and prior to puberty induction or spontaneous puberty (to avoid the effect of estrogen). The control group consisted of healthy girls without any medical history, who were matched for age and height. The study protocol was approved by the ethical committee of Ghent University Hospital. All girls and their parents gave written informed consent. All examinations were performed during a single visit to the pediatric cardiology department of Ghent University Hospital by a single experienced pediatric cardiologist (KDG).
Echocardiography Echocardiography was performed with the patient in a supine position and with the use of a VIVID 7 ultrasound (GE Vingmed Ultrasound, Horten, Norway) equipped with a 3.5 MHz probe. Data were stored and used for offline analysis by one single observer (KDG) using EchoPAC version 110.1.0 software (GE Vingmed Ultrasound). All patients and controls underwent a complete ultrasound evaluation of the heart to exclude previously unknown pathology such as abnormal aortic valve morphology or aortic coarctation. For each parameter, measurements were performed on at least 3 cardiac cycles and averaged. Diameters of the aorta were measured from the parasternal long axis at the level of the aortic valve annulus, aortic root and ascending aorta at the level of the right pulmonary artery. The interventricular septum, posterior wall and internal diameters were measured on a parasternal short axis and used for calculation of fractional shortening and Devereux index. For each variable, z-scores were calculated according to the Sluysmans data [19]. For the aortic root and ascending aorta, zscore was calculated using our own previously reported Campens formula [20]. On the parasternal long axis, an M-mode image of the ascending aorta was recorded. Care was taken to place the aorta horizontally on the screen with the cursor perpendicular to the arterial wall at the level of the right pulmonary artery. On the Mmode recording, the diameter of the ascending aorta was measured from inner to inner surface during diastole and systole (Fig. 1). The mean of 10 M-mode measurements and the mean of 3 blood pressure measurements performed during the ultrasound exam were used for calculation of the aortic stiffness index and distensibility as described below [21]
Anthropometry Body height was measured with a wall mounted stadiometer and body weight with an electronic scale. Height, weight, and body mass index (BMI) z-scores were calculated using Flemish reference growth data, and body surface area (BSA) according to Haycock’s formula [16].
2 6 Distensibility 6 4diameter 2
diast
2
h i blood pressure ln blood pressure syst diast i ðdimensionlessÞ Aortic stiffness index h diametersyst diameterdiast diameterdiast
and
diametersyst 2 2
p
diameterdiast 2
2
p
3
7 7107 ðin 103 kPa1 Þ 5 p ðblood pressuresyst blood pressurediast Þ1333
Blood pressure Blood pressure was taken at the 4 limbs, with the patient at rest and in a supine position (Accutorr Plus, Datascope, Mahwah, NJ, USA with an appropriate pediatric cuff). Additionally, blood pressure was taken 3 times at the right arm during the ultrasound examination. The mean of these 3 measurements was used for statistics and the calculation of distensibility and stiffness index. In-office blood pressure was considered normal if below the 95th percentile for sex, age, and height [17]. For Turner girls, an additional 24-h blood pressure registration was performed (Tonoport V, Par Medzintechnik, Berlin, Germany) and analyzed using the normal values for sex and age described by Wuhl et al. [18]. Abnormal nocturnal dipping was defined as:
systolic blood pressure during night time 100 < 10% 1 systolic blood pressure during day time
Fig. 1. M-mode recording of the ascending aorta on the parasternal long axis. The diameter of the ascending aorta is measured in diastole and systole.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
Vascular examination
Results
The patient was positioned with the head rotated 458 to the left. Using a vascular transducer 12L set at 10 MHz, the right carotid artery was visualized at the site of the bifurcation. The intimamedia thickness (IMT) of the far wall of the common carotid artery was measured 10 mm below the bifurcation at the end of diastole, using the automatic border detection of the EchoPAC system. The inner diameter of the carotid artery was measured at the end of diastole [22]. The mean of at least 10 measurements was used for analysis. Pulse wave (PW) Doppler signals were obtained consecutively at the right common carotid artery and the right femoral artery. The time interval (Dtime) between the arrival of the pulse at the carotid and femoral arteries was calculated using the foot-to-foot velocity method as described earlier (Fig. 2) [23]. The distance (D) was calculated as the distancecarotid arteryfemoral artery distancecarotid artery-suprasternal notch. PW velocity (V) was then defined as D/Dtime expressed in m/s. The mean of 15 Doppler measurements was used for analysis.
Study population
3
All 15 eligible TS girls agreed to participate and were enrolled in the study. Their karyotypes were 45,X (n = 6), 45,X/46,XX (n = 2), 45,X/46,XX/47,XX (n = 3), and others (n = 4). Two girls had a history of aortic coarctation that was treated surgically in the neonatal period with a good functional result. Twelve TS girls were treated with growth hormone at the time of the study (mean duration 3.4 years, range 0.5–6.5 years); none received any other medication. The control group consisted of 32 healthy prepubertal girls who were matched for age and height. One control showed a normally functioning but bicuspid aortic valve with marked dilation of the ascending aorta and was excluded from the analysis. With 15 TS patients and 31 controls, post hoc power analysis yielded a power of 94%. Data on age, body height, weight, and BMI are presented in Table 1. TS patients and controls did not differ in age and height but BMI and body weight z-score were statistically lower in the control than in the TS group.
Statistical analysis Blood pressure Statistical analysis was performed using SPSS, Statistics 23 (IBM, Chicago, IL, USA). If data were normally distributed, they were presented as mean SD and analyzed by parametric tests (unpaired t-test and ANOVA with Bonferroni post hoc analysis). If data were not normally distributed, they were presented as median (interquartile ranges) and analyzed using non-parametric tests (Kruskal–Wallis, Mann–Whitney U, and median K samples). Differences were considered statistically significant if p < 0.05.
In-office blood pressure was normal in all girls and there was no statistically significant difference between the TS patients and the controls (Table 2). All participants had higher blood pressures in the lower than in the upper limbs. Ambulatory 24-hour blood pressure values were available for 11 TS patients: 3 measurements were declined by the patient and 1 registration failed due to technical reasons. In 4 TS patients (33%), ambulatory blood pressure measurement revealed hypertension during the daytime but the mean systolic and diastolic blood pressures exceeded the normal values only mildly. Non-dipping was found in 5 patients (45%). Aortic valve morphology Aortic valve morphology (bicuspid or tricuspid) could be appreciated satisfactorily in all cases. In the TS group, 6 patients (40%) had a bicuspid aortic valve (BAV). None of the valves were stenotic or insufficient. All 31 controls had a normally functioning tricuspid aortic valve (TAV). Diameters of the aorta The ascending aorta diameters in the TS group were significantly higher than in the control group (p = 0.012). When TS girls with BAV and TAV were analyzed separately, there was only a statistically significant difference in ascending aorta size between TS patients with a BAV and the controls, both for absolute diameters (p = 0.014) and the calculated z-scores (p = 0.008)
Table 1 Biometry of the Turner syndrome and the control group.
Age (y) Weight (kg) Height (cm) BMI (kg/m2) Weight z-score Height z-score BMI z-score Fig. 2. Pulse wave (PW) Doppler signal at the femoral artery (upper part) and the common carotid artery (lower part). For both signals, the time interval is measured between the onset of the QRS complex and the onset of the systolic PW Doppler signal. Dtime is calculated as the difference between both time intervals.
Turner patients (N = 15)
Controls (N = 31)
p-value
10.6 (8.3 to 11.0) 31.2 (25.4 to 40.2) 133.4 (125.6 to 138.1) 17.53 (16.07 to 19.23) S0.8 (S1.0 to 0.3) S1.6 (S2.1 to S0.8) 0.2 (0.0 to 0.8)
10.4 (7.7 to 11.7) 27.0 (23.4 to 31.1) 130.8 (125.3 to 140.5) 15.53 (14.65 to 16.53) S1.0 (S1.9 to S0.7) S1.40 (S2.0 to S0.2) S0.6 (S1.4 to S0.2)
0.963 0.085 0.907 <0.001 0.022 0.656 <0.001
Data presented as median (interquartile ranges) or mean SD. BMI, body mass index. p-values shown in bold are considered statistically significant.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
4
Table 2 Cardiovascular data of controls versus TS patients with a TAV and a BAV.
SBP (mmHg) DBP (mmHg) AoAsc (mm) AoAsc z-score AoRoot (mm) AoRoot z-score Carotid diameter (mm) cIMT (mm) Stiffness index Distensibility (103 kPa1) PWV (m/s) Devereux index (g/m2)
Controls (N = 30)
TS TAV (N = 9)
TS BAV (N = 6)
p-value overall
p-value C–TS TAV
p-value C–TS BAV
p-value TS TAV–TS BAV
101.21 7.91 63.5 6.09 18.62 1.88 0.14 0.69 19.03 (17.88–21.72) 0.78 0.88 4.68 (4.48–4.87) 0.48 (0.46–0.51) 3.22 (2.53–3.56) 63.18 (55.52–76.96) 3.82 (3.54–4.29) 60.24 (54.49–69.18)
103.26 8.57 66.82 7.37 20.17 2.47 0.57 1.17 20.26 (19.13–21.55) 0.40 1.19 5.03 (4.48–5.33) 0.47 (0.44–0.52) 3.92 (2.98–5.99) 49.19 (33.95–66.52) 4.01 (3.77–4.48) 74.32 (60.28–77.02)
101.94 7.80 65.67 7.70 22.16 5.10 1.66 2.05 21.12 (18.79–24.97) 0.15 1.45 5.03 (4.45–5.56) 0.47 (0.45–0.52) 5.60 (4.53–6.68) 33.37 (29.41–51.05) 3.87 (3.57–4.17) 71.33 (53.13–96.81)
0.797 0.375 0.012 0.010 0.139 0.118 0.279 0.161 0.005 0.003 0.414 0.061
1.000 0.572 0.392 0.913 0.490 0.990 0.164 0.048 0.028 0.014 0.230 0.028
1.000 1.000 0.014 0.008 0.286 0.144 0.180 0.865 0.006 0.005 0.445 0.203
1 1 0.474 0.170 1 0.945 1 0.556 0.346 0.289 0.239 0.841
One distinct outlier in the control group, the older sister of the excluded control with a bicuspid valve, probably suffers from a congenital familial aortic disease and was excluded from further analysis of the aortic stiffness. Her data are not included in this table. Data presented as median (interquartile ranges) or mean SD. C, controls; TS TAV, Turner syndrome patients with a tricuspid aortic valve; TS BAV, Turner syndrome patients with a bicuspid aortic valve; SBP, systolic blood pressure; DBP, diastolic blood pressure (mean of 3 measurements during the ultrasound exam); AoAsc, ascending aorta diameter; AoRoot, aortic root diameter; cIMT, intima-media thickness of the common carotid artery; PWV, pulse wave velocity. p-values shown in bold are considered statistically significant.
(Fig. 3 and Table 2). The other aortic diameters were not statistically different between the TS and the control groups (Table 2). Distensibility and stiffness of the aortic arch The ascending aorta of TS girls showed a significantly higher stiffness index (p = 0.005) and lower distensibility (p = 0.003) than the controls (Table 2). In the control group, there was 1 distinct outlier
with a severely decreased distensibility and increased stiffness index, the older sister of the excluded control with a bicuspid valve. This girl probably suffers from a congenital familial aortic disease and was excluded from further analysis of the aortic stiffness. When TS girls with BAV and TAV were analyzed separately, a distinct difference in ascending aorta stiffness index and distensibility remained between controls and TS girls, both with BAV or TAV (Table 2 and Fig. 4).
Fig. 3. Absolute (mm, panel A) and relative (z-score, panel B) ascending aorta diameters for the 3 groups. Turner syndrome (TS) with TAV: patients with TS and a tricuspid aortic valve. TS with BAV: patients with TS and a bicuspid aortic valve.
Fig. 4. Stiffness index (panel A), distensibility (panel B), and PWV (panel C) in the control group versus the TS group with TAV and BAV. PWV, pulsed wave velocity; TS, Turner syndrome; TAV, tricuspid aortic valve; BAV, bicuspid aortic valve.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
Pulse wave velocity between the carotid and femoral arteries did not show any significant difference between groups (Table 2 and Fig. 4). Two TS girls, one with a BAV and one with a TAV, were previously surgically treated for coarctation. To exclude the impact of coarctation on the elasticity parameters, we repeated the analysis without those 2 girls. The statistically significant difference between TS patients and controls remained for stiffness index (p = 0.022) and distensibility (p = 0.012). Carotid artery There was neither statistically significant difference in carotid artery diameter nor in IMT between the Turner and the control group (Table 2). Cardiac function There was no statistically significant difference in parameters of systolic or diastolic function between the groups. Only the cardiac mass, expressed as the Devereux index, was slightly higher in the TS TAV group compared to controls (Table 2). Discussion This is the first report on aortic distensibility and stiffness in a non-selected group of young prepubertal TS girls. Our data show an increased stiffness and decreased distensibility of the ascending aorta of young TS girls with a BAV and TAV whereas severe aortic dilation was restricted to TS girls with a BAV. This suggests that TS girls have an aortic wall abnormality that is inherent to the genetic problem and that, although progressive with age, aortic dilation should be considered a congenital cardiovascular defect. Although the literature contains a large amount of data on aortic pathology in TS, the interpretation of most studies is complicated by non-homogenous study populations, the presence of comorbidity, and the intake of multiple drugs. In addition, the physiological influence of age on the aortic wall and the possible impact of estrogen deficiency and hormone replacement therapy on aortic wall properties are not always taken into account. This study was conducted to overcome at least some of these interfering factors. All TS girls were prepubertal to minimize the possible effect of estrogen deficiency in the development of aortic dilation. In this young age group, there was no co-morbidity of diabetes, thyroid dysfunction, metabolic syndrome, or severe hypertension and there was no interference of medical therapy other than growth hormone. In our study group, the youngest studied to date, we found significantly larger diameters in the TS group at the site of the ascending aorta. However, when the aortic valve morphology was taken into account, dimensions were only significantly larger in those with a BAV. Enlarged aortic dimensions in pediatric TS patients were reported previously [7,8]. Lopez et al. described that a BAV is a risk factor for aortic dilation in childhood. In contrast to our findings, they also found larger aortas in TS patients with a normal aortic valve, but unlike ours, their study population contained both pubertal and prepubertal girls [8]. In our prepubertal girls, either with a BAV or a TAV, the ascending aorta was significantly stiffer than those of the healthy controls. Pulse wave velocity between the right carotid and right femoral artery was not different between TS and controls, suggesting a similar elasticity along the total length of the aorta and a selective disease of the proximal part of the aorta, independent of aortic valve morphology. This finding is in line with the results of post mortem studies in TS women after aortic rupture that describe type A dissections in 2/3 of the cases
5
[11,24]. An alternative explanation for the discrepancy between the M-mode and the PWV results could be found in the method of the ultrasound PWV measurement. The distance traveled by the pulse is measured with a tape measure from the carotid to the femoral measuring site. This however presumes a normal aortic arch morphology without elongation or abnormal kinking. As adult TS patients often have an abnormal arch morphology [5,25,26], the tape measure is possibly not representative for the aortic length and underestimates the real distance traveled by the pulse. In our study population, 6 TS girls (40%) had a BAV compared to the 12–39% described in the literature [3,6,8,27–30]. In the general population, BAV are associated with dilation of the aortic root and the ascending aorta that can lead to aortic dissection and rupture. They are also associated with impaired aortic elasticity, independently of the presence of aortic dilation [31,32]. The abnormal elasticity of the ascending aorta in our young TS patients however was not restricted to TS patients with a BAV. This suggests that the abnormal aortic wall property in TS is a primary defect and not secondary to the presence of a BAV. This finding is in line with data in adults describing rapid aortic growth and aortic rupture in TS women with a normal TAV [33]. Although not statistically significant, elasticity in TS patients with a BAV was more impaired than in those with a TAV, suggesting an additive effect of BAV and an intrinsic wall abnormality. Coarctation is reported in 4–15% of TS patients [3,5,27,28,30] and is known to cause aortic dilation, abnormal arch morphology, and increased proximal aortic stiffness [34–36]. Our TS group contained 2 girls with a coarctation that was treated in the neonatal period. To examine a possible bias due to the coarctation, analysis was repeated after exclusion of these two patients, but this did not influence the results. In-office blood pressure measurements were normal in all participants and there was no difference in systolic or diastolic blood pressure between the study and the control groups. However, on 24-h blood pressure measurement, hypertension was found in 4 girls and abnormal nocturnal dipping in 5. The number of patients was insufficient to examine the influence of 24h blood pressure on aortic diameters or elasticity. Vascular pathology in TS is not limited to the aorta. Ostberg et al. also showed an increased diameter of the carotid artery and a thicker intima-media thickness in adult TS women compared to normal controls [37]. In a younger TS population, the increase in IMT was not observed [15,38]. Our study could not find a difference in IMT or carotid diameter between young TS girls and matched controls. This probably can be explained by the young age of our TS study group and cannot rule out possible progression in the future. The major limitations of this study are the small number of patients included, the possible interference with growth hormone, and the lower body weight of the control group. TS is frequently diagnosed during adolescence, making it difficult to recruit prepubertal patients. In our study group of 15 patients, the diagnosis of TS was made at a young age with a prenatal diagnosis in 5 of them. We cannot rule out that this caused a selection bias toward the more severe TS phenotypes. Twelve TS girls (80%) received standard doses of growth hormone. Due to ethical considerations, it was impossible to stop this treatment for a long period. There are however little indications that growth hormone has a detrimental influence on aortic elasticity or aortic dimensions. In a prospective study, Lawson et al. could not find an association between vasculopathy and growth hormone treatment in TS girls [15]. Bondy et al. did not find a difference in heightcorrected aortic diameters in TS who received (or had received) growth hormone compared to those who did not receive (or had not received) growth hormone [39]. Van den Berg et al. found an impaired aortic elasticity in adult TS patients but those who received high doses of growth hormone during childhood and
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx
6
adolescents showed an elasticity that was comparable to the normal [40]. The results presented here indicate an increased stiffness of the ascending aorta from early age on, both in TS patients with a TAV and BAV, and earlier ascending aorta dilation in those with a BAV. These data support the idea that all TS patients are at increased risk for severe aortic complications, but that the risk of those with a BAV is the highest. Follow-up studies are needed to see if young patients with increased aortic stiffness but currently normal diameters evolve toward dilation at an older age. Secondly, the question remains if increased stiffness leads to a higher risk for dissection and rupture even in the absence of severe dilation. Probably other TS-related factors such as hypertension, dyslipidemia, diabetes, or pregnancy play an additional role. Conclusions In prepubertal TS girls, the stiffness of the ascending aorta is increased in patients with a BAV and a TAV while dilation of the ascending aorta is more frequent in those with a BAV. These data suggest an intrinsic abnormal aortic wall property in TS patients making them all at risk for severe aortic complications although the risk is the highest for those with a BAV. If increased stiffness plays an important role in the evolution toward dissection, it might be useful to include measurement of distensibility and stiffness in the risk assessment of TS patients. Large prospective studies however are needed to support this hypothesis. Funding Daniel Devos is recipient of a KOF clinical fellowship nr AB/SDS/ 799/2008/hdp from the University Hospital Ghent. Danilo Babin is recipient of IWT (Spin-off) Innovation Mandate 130865. Disclosure statement None of the authors have relationships with industry to disclose, nor any conflict of interest relevant to the contents of this paper. Author contributions Each of us acknowledges that he or she participated sufficiently in the work to take public responsibility for its content References [1] Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. [2] Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA. Mortality in women with turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab 2008;93:4735–42. [3] Gotzsche CO, Krag-Olsen B, Nielsen J, Sorensen KE, Kristensen BO. Prevalence of cardiovascular malformations and association with karyotypes in Turner’s syndrome. Arch Dis Child 1994;71:433–6. [4] Gravholt CH. Clinical practice in Turner syndrome. Nat Clin Pract Endocrinol Metab 2005;1:41–52. [5] Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, Bondy CA. Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features. Circulation 2004;110:1694–700. [6] Mazzanti L, Prandstraller D, Fattori R, Lovato L, Cicognani A, Italian Study Group for Turner Syndrome. Monitoring of congenital heart disease (CHD) and aortic dilatation in Turner syndrome: Italian experience. Int Congr Series 2006;1298:123–30. [7] Chalard F, Ferey S, Teinturier C, Kalifa G. Aortic dilatation in Turner syndrome: the role of MRI in early recognition. Pediatr Radiol 2005;35:323–6.
[8] Lopez L, Arheart KL, Colan SD, Stein NS, Lopez-Mitnik G, Lin AE, Reller MD, Ventura R, Silberbach M. Turner syndrome is an independent risk factor for aortic dilation in the young. Pediatrics 2008;121:e1622–27. [9] Nathwani NC, Unwin R, Brook CG, Hindmarsh PC. Blood pressure and Turner syndrome. Clin Endocrinol (Oxf) 2000;52:363–70. [10] De Groote K, Demulier L, De Backer J, De Wolf D, De Schepper J, T’sjoen G, De Backer T. Arterial hypertension in Turner syndrome: a review of the literature and a practical approach for diagnosis and treatment. J Hypertens 2015;33: 1342–51. [11] Carlson M, Airhart N, Lopez L, Silberbach M. Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the international turner syndrome aortic dissection registry. Circulation 2012;126:2220–6. [12] Gravholt CH, Landin-Wilhelmsen K, Stochholm K, Hjerrild BE, Ledet T, Djurhuus CB, Sylve´n L, Baandrup U, Kristensen BØ, Christiansen JS. Clinical and epidemiological description of aortic dissection in Turner’s syndrome. Cardiol Young 2006;16:430–6. [13] Mortensen KH, Hjerrild BE, Stochholm K, Andersen NH, Sorensen KE, Lundorf E, Hørlyck A, Pedersen EM, Christiansen JS, Gravholt CH. Dilation of the ascending aorta in Turner syndrome – a prospective cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2011;13:24. [14] Sharma J, Friedman D, Dave-Sharma S, Harbison M. Aortic distensibility and dilation in Turner’s syndrome. Cardiol Young 2009;19:568–72. [15] Lawson SA, Urbina EM, Gutmark-Little I, Khoury PR, Gao Z, Backeljauw PF. Vasculopathy in the young Turner syndrome population. J Clin Endocrinol Metab 2014;99:E2039–45. [16] Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr 1978;93:62–6. [17] National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114(2 Suppl. 4th Report):555–76. [18] Wuhl E, Witte K, Soergel M, Mehls O, Schaefer F. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens 2002;20:1995–2007. [19] Sluysmans T, Colan SD. Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 2005;99:445–57. [20] Campens L, Demulier L, De Groote K, Vandekerckhove K, De Wolf D, Roman MJ, Devereux RB, De Paepe A, De Backer J. Reference values for echocardiographic assessment of the diameter of the aortic root and ascending aorta spanning all age categories. Am J Cardiol 2014;114:914–20. [21] Hauser M, Kuhn A, Petzuch K, Wolf P, Vogt M. Elastic properties of the ascending aorta in healthy children and adolescents. Age-related reference values for aortic wall stiffness and distensibility obtained on M-mode echocardiography. Circ J 2013;77:3007–14. [22] Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, Jacobson M, Mahoney L, Mietus-Snyder M, Rocchini A, Steinberger J, McCrindle B, American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension 2009;54:919–50. [23] Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H, European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006;27:2588–605. [24] Bondy CA. Aortic dissection in Turner syndrome. Curr Opin Cardiol 2008;23: 519–26. [25] De Groote K, Devos D, Van Herck K, Demulier L, Buysse W, De Schepper J, De Wolf D. Abnormal aortic arch morphology in Turner syndrome patients is a risk factor for hypertension. Heart Vessels 2015;30:618–25. [26] Mortensen KH, Hjerrild BE, Andersen NH, Sorensen KE, Horlyck A, Pedersen EM, Lundorf E, Christiansen JS, Gravholt CH. Abnormalities of the major intrathoracic arteries in Turner syndrome as revealed by magnetic resonance imaging. Cardiol Young 2010;20:191–200. [27] Douchin S, Rossignol AM, Klein SK, Siche JP, Baguet JP, Bost M. Heart malformations and vascular complications associated with Turner’s syndrome. Prospective study of 26 patients. Arch Mal Coeur Vaiss 2000;93: 565–70. [28] Prandstraller D, Mazzanti L, Picchio FM, Magnani C, Bergamaschi R, Perri A, Tsingos E, Cacciari E. Turner’s syndrome: cardiologic profile according to the different chromosomal patterns and long-term clinical follow-up of 136 nonpreselected patients. Pediatr Cardiol 1999;20:108–12. [29] Sybert VP. Cardiovascular malformations and complications in Turner syndrome. Pediatrics 1998;101:E11. [30] Kim HK, Gottliebson W, Hor K, Backeljauw P, Gutmark-Little I, Salisbury SR, Racadio JM, Helton-Skally K, Fleck R. Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population. Am J Roentgenol 2011;196: 454–60. [31] Moaref A, Khavanin M, Shekarforoush S. Aortic distensibility in bicuspid aortic valve patients with normal aortic diameter. Ther Adv Cardiovasc Dis 2014;8: 128–32.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006
G Model
JJCC-1285; No. of Pages 7 K. De Groote et al. / Journal of Cardiology xxx (2016) xxx–xxx [32] Oulego-Erroz I, Alonso-Quintela P, Mora-Matilla M, Gautreaux Minaya S, ˜ a-Lo´pez de Armentia S. Ascending aorta elasticity in children with Lapen isolated bicuspid aortic valve. Int J Cardiol 2013;168:1143–6. [33] Carlson M, Silberbach M. Dissection of the aorta in Turner syndrome: two cases and review of 85 cases in the literature. J Med Genet 2007;44:745–9. [34] Ou P, Bonnet D, Auriacombe L, Pedroni E, Balleux F, Sidi D, Mousseaux E. Late systemic hypertension and aortic arch geometry after successful repair of coarctation of the aorta. Eur Heart J 2004;25:1853–9. [35] Ou P, Mousseaux E, Celermajer DS, Pedroni E, Vouhe P, Sidi D, Bonnet D. Aortic arch shape deformation after coarctation surgery: effect on blood pressure response. J Thorac Cardiovasc Surg 2006;132:1105–11. [36] Ou P, Celermajer DS, Raisky O, Jolivet O, Buyens F, Herment A, Sidi D, Bonnet D, Mousseaux E. Angular (Gothic) aortic arch leads to enhanced systolic wave reflection, central aortic stiffness, and increased left ventricular mass late after
[37]
[38]
[39] [40]
7
aortic coarctation repair: evaluation with magnetic resonance flow mapping. J Thorac Cardiovasc Surg 2008;135:62–8. Ostberg JE, Donald AE, Halcox JP, Storry C, McCarthy C, Conway GS. Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction. J Clin Endocrinol Metab 2005;90:5161–6. Radetti G, Mazzanti L, Di Somma C, Salerno M, Gottardi E, Capalbo D, Tamburrino F, Colao A. Evaluation of function and structure of arterial wall in girls and young women with Turner syndrome. J Endocrinol Invest 2015;38:963–70. Bondy CA, Van PL, Bakalov VK, Ho VB. Growth hormone treatment and aortic dimensions in Turner syndrome. J Clin Endocrinol Metab 2006;91:1785–8. van den Berg J, Bannink E, Wielopolski P, Pattynama PM, de Muinck KeizerSchrama SM, Helbing W. Aortic distensibility and dimensions and the effects of growth hormone treatment in the turner syndrome. Am J Cardiol 2006;97:1644–9.
Please cite this article in press as: De Groote K, et al. Increased aortic stiffness in prepubertal girls with Turner syndrome. J Cardiol (2016), http://dx.doi.org/10.1016/j.jjcc.2016.03.006