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Hypertension occurs in many patients with Turner syndrome (TS), probably approaching 50% in aging populations. Hypertension seems to be of the essential type, although the reason for the high frequency is unknown. Hypertension should be looked for, and treated appropriately. Hypertension is probably linked to the frequent occurrence of aortic dissection in TS. Presently, the best drug of choice has not been identified, but usually beta-blockers are recommended. Lipid disorders may be present in some patients and should be treated according to international guidelines. Other risk factors, like an unfavourable body composition should also be looked for and prevented. The presence of ischemic heart disease is increased, and should be monitored during clinical care.
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Hypertension and ischemic cardiovascular disease in
Turner syndrome
Claus Højbjerg Gravholt , Britta Hjerrild
Medical Department M (Endocrinology and Diabetes), Aarhus Sygehus, Nørrebrogade,
Aarhus University Hospital, DK-8000 Aarhus C, Denmark
Abstract. Hypertension occurs in many patients with Turner syndrome (TS), probably approaching
50% in aging populations. Hypertension seems to be of the essential type, although the reason for the
high frequency is unknown. Hypertension should be looked for, and treated appropriately.
Hypertension is probably linked to the frequent occurrence of aortic dissection in TS. Presently, the
best drug of choice has not been identified, but usually beta-blockers are recommended. Lipid
disorders may be present in some patients and should be treated according to international
guidelines. Other risk factors, like an unfavourable body composition should also be looked for and
prevented. The presence of ischemic heart disease is increased, and should be monitored during
clinical care. © 2006 Published by Elsevier B.V.
Keywords: Epidemiology; Morbidity, diagnosis; Mortality; Prevalence; Incidence; Delay
1. Introduction
The presence of congenital malformations such as coarctation of the aorta, horse shoe
kidney and pterygium colli in Turner syndrome (TS) is well known, as well as less severe
congenital malformations of the heart, especially with the 45,X karyotype. The prevalence
and the nature of cardiovascular malformations have been described in several studies [13].
The malformations normally involve only the vessels of the left side of the heart, and show a
very characteristic pattern when compared with the general population. However, with the
possibility of compounding these congenital malformations, it is becoming increasingly
clear that hypertension and ischemic heart disease probably also are inherent features of TS.
Here, we review the evidence concerning hypertension and ischemic heart disease.
International Congress Series 1298 (2006) 174 179
www.ics-elsevier.com
Corresponding author. Tel.: +45 89 49 20 57; fax: +45 89 49 20 10.
E-mail address: ch.gravholt@dadlnet.dk (C.H. Gravholt).
0531-5131/ © 2006 Published by Elsevier B.V.
doi:10.1016/j.ics.2006.06.005
2. Hypertension
Thirty percent of girls with Turner syndrome are mildly hypertensive on 24-h
ambulatory blood pressure monitoring, and 50% have an abnormal diurnal blood pressure
profile [4].
Women with Turner syndrome have significantly elevated blood pressure compared
with an age matched control group [5], and as many as 50% have clinical hypertension
[6,7]. Treatment with sex hormones caused a significant reduction in the 24-h diastolic and
the diastolic day pressure, and a near significant fall in systolic day pressure [5], which we
have recently confirmed in a smaller group of patients [8]. The diastolic night/day ratio was
elevated compared with controls and increased even further with HRT, as did systolic night/
day ratio [5]. The significance of this is difficult to interpret. It is thus evident that women
with Turner syndrome are non-dippers, i.e., have a diminished reduction of blood
pressure during the night [4,5,8].Non-dippingin hypertensive women is a predictor of
future cardiovascular events. Twenty-four-hour, day, and night heart rate has been found
significantly elevated in Turner syndrome compared to controls [5], which could be
suggestive of the presence of parasympathetic neuropathy.
Hypertension in Turner syndrome seems to be essential by nature. At least there is only
scant scientific data to suggest that the usual hypertensive female with TS suffers from
secondary hypertension. Plasma renin activity has been found to be elevated in
approximately 50% of TS girls by some [9,10], whereas others have found normal plasma
renin activity and aldosterone levels, as well as normal urinary albumin secretion [8].In
addition, circulating catecholamines are thought to be normal. Renal function is normal in
TS in most cases, despite the high frequency of renal malformations [11].
Recently, we found signs of altered autonomic innervation of the heart in TS. Using a
battery of conventional bedside tests we found normal cardiovascular responses in
comparison with age-matched controls. However, when using short-term spectral
analysis of heart rate variability, which is a more sensitive method than bedside tests for
detection of early autonomic neuropathy, we found an impaired sympatho-vagal balance
or tone in TS [8]. As also found previously, we found an increased heart rate in TS, as
well as an impaired response to changing from a supine to a standing position in a
combined measure of vagal and sympathetic innervation of the heart. The aetiology
behind the defective sympathovagal balance in TS is not clear [8]. In the same study, we
also found elevated levels of N-terminal pro-brain natriuretic peptide (BNP), a marker
linked to heart failure.
Previous and recent ECG findings show a prolonged QTc segment, suggesting that
cardiac conduction and repolarization abnormalities are also intrinsic features of TS
[12,13].
Presently there are no longitudinal studies of blood pressure and hypertension in Turner
syndrome. There is a definite need for such studies. Furthermore, it is essential to establish
the effect of treatment and to determine which drugs to choose as first and second line
treatment. The choice of anti-hypertensive drugs is so far based on extrapolations from the
experience with Marfan syndrome, and beta-blockers are considered first drug-of-choice,
especially given the common tachycardia in TS. In Marfan syndrome, beta-blockers have
been shown to be effective in lowering blood pressure and delaying aortic dilatation [14].
175C.H. Gravholt, B. Hjerrild / International Congress Series 1298 (2006) 174179
However, no prospective studies have documented the efficacy of either beta-blockade or
modulation of the ACE/AT-II system in TS.
3. Ischemic cardiovascular disease
3.1. Cholesterol profile
Previously, ischemic heart disease has not been found with increased frequency in
Turner syndrome, despite reports of increased levels of cholesterol [15], increased blood
pressure, and congenital cardiac malformations.
An epidemiological study found an increased frequency of ischemic heart disease (acute
myocardial infarction, and arteriosclerosis) [16]. The relative risk (RR) of disease was
increased to 2.1 (95% confidence interval (CI): 1.23.4), while hypertension occurred with
a RR of 2.9 (95% CI: 1.26.0), and cerebrovascular diseases of 2.7 (95% CI: 1.045.3).
Likewise mortality due to cardiovascular causes is elevated in TS [17].
In a clinical study, we could not detect any difference in measures of lipid status between
a group of untreated women with Turner syndrome before treatment and a control group
[5,18], also corroborated by others [19], while others, using a different approach in
choosing control groups have reached different results. Ostberg et al. used women with
premature ovarian failure (POF) as controls, in addition to normal controls, and found an
essentially comparable cholesterol profile, including triglycerides, to the cholesterol profile
in TS, while normal controls had lower levels of cholesterol [20]. Van et al., using the same
approach with a POF control group, found an elevated cholesterol profile in TS [21], with a
reduced LDL size, suggesting a more atherogenic lipid profile. Suffice to say, additional
research is necessary to conclude whether the lipid profile in TS is normal or elevated.
Compensated hypothyreosis is, however, often a problem in TS, and is associated with
coronary artery disease, and elevated fractions of cholesterol [22]. This may help explain
part of the increased risk of cardiovascular disease in Turner syndrome [16], since
hypothyreosis and thyroid antibody formation is common in Turner syndrome.
3.2. Left ventricular function
Since women with TS are at risk of not only congenital cardiovascular malformations
but also hypertension and ischemic heart disease, left ventricular (LV) performance may
also be perturbed. Conventional echocardiography, however, has not been able to identify
LV dysfunction in TS [1,23] but the techniques used may well have been insufficient to
detect subtle alterations in cardiac function.
We have recently introduced tissue Doppler echocardiography in the study of LV
function in TS, which is more sensitive in detection of the early phases of systolic
dysfunction, particularly in the assessment of longitudinal myocardial dysfunction. [24,25].
We examined 33 young, normotensive, healthy TS, only using HRT, and 33 age-matched
controls, and found LV diastolic dysfunction in more than a quarter of the women with TS
[38]. It is quite remarkable to find diastolic dysfunction in such a young group of women,
normally only present in patients with considerable LV hypertrophy [26], myocardial
infarction or reduced LV ejection fraction [27]. The presence of diastolic dysfunction was
176 C.H. Gravholt, B. Hjerrild / International Congress Series 1298 (2006) 174179
closely related to the increased heart rate seen in TS, possibly related to some degree of
autonomic cardiac neuropathy (see above). Systolic LV function was also impaired in the
TS group, and closely related to the impaired diastolic function. The coexistence of
impaired relaxation and decreased systolic performance has previously been seen in
hypertensive patients and in patients with diabetes mellitus, irrespective of blood pressure
levels [28]. In such cases, the presence of increased LV mass concomitant with poorer
metabolic control seems explanatory [29]. However, in this population of normotensive
women with TS, only a vague relation between the metabolic control and markers of left
atrial (LA) pressure (LA index and the A-wave velocity) was seen. Similarly, no relations
between LV systolic performance and metabolic control or LV geometry were found. This
may relate to the narrow range of normal insulin sensitivity in this group. In contrast, LV
global stiffening was reflected in both diastolic and systolic performance, determined by
two different modalities (Fig. 1). Myocardial stiffening in women with TS may be due to an
intrinsic myocardial component, which could be a primary defect in TS leading to left
ventricular inadequacy over time [30].
3.3. Other cardiovascular risk factors
C-reactive peptide (CRP) is a marker of a chronic inflammatory state, as often found in
ischemic heart disease, and has been found to be elevated in TS [20,31]. Likewise, Ostberg
et al. found elevated levels of interleukin-6 (IL-6), a marker linked to both visceral fat and
ischemic heart disease. We have recently corroborated these findings, and in addition, we
found elevated levels of other adipokines like IL-8 and TNF-α, but paradoxically normal
levels of adiponectin (unpublished observations, CH Gravholt et al.).
In addition, body composition in TS is profoundly changed. Fat mass and body mass
index have been found to be higher in adult Turner patients compared with age matched
controls, and lean body mass (LBM) is inappropriately low [32,33]. In addition, distinct
Fig. 1. Correlation between systolic strain rate and velocity flow propagation (a measure of diastolic function) in
women with Turner syndrome.
177C.H. Gravholt, B. Hjerrild / International Congress Series 1298 (2006) 174179
differences in regional body composition is present in young TS girls (915 years) in
comparison with age- and BMI-matched controls in two different study groups [34,35],
and in adults excess visceral fat and hepatic adipose tissue has been documented [36],
and imprinting of the one X chromosome, with inheritance of the maternal X
chromosome being more deleterious, has also been suggested [37]. TS has therefore
been characterized as a syndrome of disproportionate anthropometry and body
composition [35].
4. Conclusion
Hypertension occurs in many patients with TS, probably approaching 50% in aging
populations. Hypertension should be looked for, and treated appropriately. Lipid disorders
may be present in some patients and should be treated according to international guidelines.
Other risk factors, like an unfavourable body composition should also be looked for and
prevented. The presence of ischemic heart disease is increased, and should be monitored
during clinical care.
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... Pada monitoring tekanan darah selama 24 jam, didapatkan 30% pasien TS dengan hipertensi ringan, dan 50% memiliki profil tekanan darah diurnal abnormal. 15 Pasien TS harus dilakukan pengukuran tekanan darah secara rutin. Kelengahan kita dalam mendeteksi hipertensi, menambah mortalitas kardiovaskular. ...
... 2,5 Tidak tampak hubungan antara hipertensi dengan kariotip, dan diduga hal ini terjadi sekunder karena penyakit renovaskular pada pembuluh darah kecil. 2,15 Pada penelitian ini terdapat 1 pasien menderita hipertensi dengan diagnosis adrenal insidentaloma. ...
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The aim of the study was to establish the prevalence of cardiovascular malformations in females with Turner's syndrome and analyse possible associations with the various karyotypes. One hundred and seventy nine of 393 females who had Turner's syndrome diagnosed in Denmark were examined. Complete chromosome analysis was available in all cases. Clinical examination, electrocardiography, and echocardiography including Doppler were performed. The distribution of the various karyotypes was 45,X, 58%; mosaic monosomy X, 35%; and structural abnormalities of the X chromosome, 7%. In 46 (26%) of the females a total of 69 cardiovascular malformations were found; aortic valve abnormality (18%) and aortic coarctation (10%) being the most common. There was a significant difference in the prevalence of cardiovascular malformations between 45,X and mosaic monosomy X (38% v 11%), primarily due to a significant difference in the prevalence of aortic valve abnormalities and aortic coarctation. Pulmonary valve abnormalities were seen only in females with mosaic monosomy X but the prevalence was low (3%). No patient with structural abnormalities of the X chromosome had cardiovascular malformations.
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To assess whether subclinical hypothyroidism is associated with changes in lipoprotein fractions, 13 patients maintained in a stable state of subclinical hypothyroidism for at least 3 months were studied prior to and 2 and 4 months following restoration of a euthyroid state with incremental levothyroxine sodium therapy. Thyrotropin levels ( +/- SEM) had decreased from 16.6 +/- 3.2 mU/L to 3.1 +/- 0.7 mU/L and 3.2 +/- 0.7 mU/L at 2 months and 4 months. At 2 months, levothyroxine treatment led to a decrease in levels of total cholesterol from 5.5 +/- 0.3 mmol/L (213 +/- 12 mg/dL) to 4.8 +/- 0.3 mmol/L (186 +/- 12 mg/dL), in low-density lipoprotein cholesterol (LDL-C) from 3.7 +/- 0.3 mmol/L (143 +/- 12 mg/dL) to 2.9 +/- 0.3 mmol/L (112 +/- 12 mg/dL), and in apolipoprotein B from 91 +/- 8 mg/dL to 74 +/- 7 mg/dL. At 4 months, levels of LDL-C and apolipoprotein B remained significantly lower than pretreatment values (2.9 +/- 0.2 mmol/L [112 +/- 8 mg/dL] and 75 +/- 6 mg/dL, respectively). While high-density lipoprotein cholesterol (HDL-C), HDL3-C, and apolipoprotein A-I were not significantly affected by levothyroxine therapy, there was a slight trend of increase in HDL2-C during levothyroxine substitution. There was also a tendency for a decrease in triglyceride levels from 1.3 +/- 0.2 mmol/L (115 +/- 18 mg/dL) to 0.9 +/- 0.1 mmol/L (80 +/- 9 mg/dL) at 4 months of levothyroxine therapy. Levels of HDL-C tended to decrease from 4.8 +/- 0.4 mmol/L (186 +/- 15 mg/dL) to 4.5 +/- 0.5 mmol/L (174 +/- 19 mg/dL) at 2 months and to 3.9 +/- 0.4 mmol/L (151 +/- 15 mg/dL) at 4 months. The LDL-C/HDL-C ratio also decreased from 3.3 +/- 0.3 mmol/L (128 +/- 12 mg/dL) to 2.9 +/- 0.5 mmol/L (112 +/- 19 mg/dL) and 2.5 +/- 0.3 mmol/L (97 +/- 12 mg/dL) at 2 months and 4 months, respectively. These results suggest that long-term levothyroxine therapy in patients with subclinical hypothyroidism is associated with a decrease in LDL-C and apolipoprotein B levels that are reflected in a trend of decreases in cholesterol/HDL-C and LDL-C/HDL-C ratios known to have a relationship with coronary artery disease.
Article
Objective: There is a high prevalence of congenital heart defects in patients with Turner’s syndrome. Few studies have reported echocardiographic data in unselected patients according to the different chromosomal patterns. The aim of our study was to evaluate a large series of patients with Turner’s syndrome, comparing these data with those of the general population. Methods: Five hundred ninety-four patients with Turner’s syndrome, aged 1 month to 24 years, in the Italian Study Group for Turner Syndrome underwent full cardiologic evaluation. Karyotype distribution was: 45,X (54%), X-mosaicism (13%), and X-structural abnormalities (33%). Results: The prevalence of cardiac malformations was 23%. Bicuspid aortic valve (12.5%), aortic coarctation (6.9%), and aortic valve disease (3.2%) were the most prevalent malformations. In comparison with the general population, partial anomalous pulmonary venous drainage had the highest relative risk. A correlation was found between type of congenital heart defect and karyotype. The patients with 45,X karyotype had the greatest prevalence of partial anomalous pulmonary venous drainage and aortic coarctation, whereas bicuspid aortic valve and aortic valve disease were more common in the patients with X-structural abnormalities. The patients with severe dysmorphic signs showed a significantly higher relative risk of cardiac malformations. Conclusion: X-linked factors may be involved in determining cardiac defects in Turner’s syndrome. (J Pediatr 1998;133:688-92)
Article
The spectrum of left ventricular geometric adaptation to hypertension was investigated in 165 patients with untreated essential hypertension and 125 age- and gender-matched normal adults studied by two-dimensional and M-mode echocardiography. Among hypertensive patients, left ventricular mass index and relative wall thickness were normal in 52%, whereas 13% had increased relative wall thickness with normal ventricular mass ("concentric remodeling"), 27% had increased mass with normal relative wall thickness (eccentric hypertrophy) and only 8% had "typical" hypertensive concentric hypertrophy (increase in both variables). Systemic hemodynamics paralleled ventricular geometry, with the highest peripheral resistance in the groups with concentric remodeling and hypertrophy, whereas cardiac index was super-normal in those with eccentric hypertrophy and low normal in patients with concentric remodeling. The left ventricular short-axis/long-axis ratio was positively related to stroke volume (r = 0.45, p less than 0.001), with cavity shape most elliptic in patients with concentric remodeling and most spheric in those with eccentric hypertrophy. Normality of left ventricular mass in concentric remodeling appeared to reflect offsetting by volume "underload" of the effects of pressure overload, whereas eccentric hypertrophy was associated with concomitant pressure and volume overload. Thus, arterial hypertension is associated with a spectrum of cardiac geometric adaptation matched to systemic hemodynamics and ventricular load. Concentric left ventricular remodeling and eccentric hypertrophy are more common than the typical pattern of concentric hypertrophy in untreated hypertensive patients.
Article
To assess whether subclinical hypothyroidism is associated with changes in lipoprotein fractions, 13 patients maintained in a stable state of subclinical hypothyroidism for at least 3 months were studied prior to and 2 and 4 months following restoration of a euthyroid state with incremental levothyroxine sodium therapy. Thyrotropin levels (±SEM) had decreased from 16.6±3.2 mU/L to 3.1±0.7 mU/L and 3.2±0.7 mU/L at 2 months and 4 months. At 2 months, levothyroxine treatment led to a decrease in levels of total cholesterol from 5.5±0.3 mmol/L (213±12 mg/dL) to 4.8±0.3 mmol/L (186±12 mg/dL), in low-density lipoprotein cholesterol (LDL-C) from 3.7±0.3 mmol/L (143±12 mg/dL) to 2.9±0.3 mmol/L (112±12 mg/dL), and in apolipoprotein B from 91±8 mg/dL to 74±7 mg/dL. At 4 months, levels of LDL-C and apolipoprotein B remained significantly lower than pretreatment values (2.9±0.2 mmol/L [112±8 mg/dL] and 75±6 mg/dL, respectively). While high-density lipoprotein cholesterol (HDL-C), HDL3-C, and apolipoprotein A-I were not significantly affected by levothyroxine therapy, there was a slight trend of increase in HDL2-C during levothyroxine substitution. There was also a tendency for a decrease in triglyceride levels from 1.3±0.2 mmol/L (115±18 mg/dL) to 0.9±0.1 mmol/L (80±9 mg/dL) at 4 months of levothyroxine therapy. Levels of HDL-C tended to decrease from 4.8±0.4 mmol/L (186±15 mg/dL) to 4.5±0.5 mmol/L (174±19 mg/dL) at 2 months and to 3.9±0.4 mmol/L (151±15 mg/dL) at 4 months. The LDL-C/HDL-C ratio also decreased from 3.3±0.3 mmol/L (128±12 mg/dL) to 2.9±0.5 mmol/L (112±19 mg/dL) and 2.5±0.3 mmol/L (97±12 mg/dL) at 2 months and 4 months, respectively. These results suggest that long-term levothyroxine therapy in patients with subclinical hypothyroidism is associated with a decrease in LDL-C and apolipoprotein B levels that are reflected in a trend of decreases in cholesterol/HDL-C and LDL-C/HDL-C ratios known to have a relationship with coronary artery disease.
Unlabelled: Adult Turner syndrome (TS) patients frequently present hypertension. To clarify the pathogenesis of this hypertension we examined the blood pressure (BP) behaviour and the renin-angiotensin-aldosterone system in 31 TS patients (2-22 years of age). BP levels were occasionally elevated in 47% of the subjects and constantly elevated in 23%. Most of the patients were on estrogen replacement therapy, but 26% of them presented with elevated levels since childhood. Supine and upright plasma renin activity (PRA) values were higher in TS compared to controls and more elevated in hypertensive TS than in the normotensive ones. At Captopril challenge TS showed different PRA responses regardless of the karyotype and clinical features. Patients on estrogen therapy, however, exhibited higher increments of PRA after Captopril. Conclusions: TS patients show high frequency of hypertension in pediatric age. Estrogen therapy is an outbreaking and worsening factor. An estrogen independent role of the renin-angiotensin-aldosterone system in the pathogenesis of TS hypertension is still uncertain.
Article
A further study of the electrocardiogram in patients with sex chromosome abnormalities who have no evidence of heart disease is described. It is confirmed that in 47, XYY males the atrioventricular conduction is delayed and that in 45, X females it is accelerated. In 47, XYY males there is also a higher than normal frequency of minor defects of intraventricular conduction. No significant deviation from normal was found in the electrocardiogram of men with a 47, XXY karyotype or in 47, XXX women. The significance of the finding is discussed.
Article
Turner syndrome is associated with insulin resistance, increased incidence of type II diabetes, and hypertension, all of which are cardiovascular risk factors. The purpose of this study was to evaluate the lipid profile of girls with untreated Turner syndrome, (aged 5 to 14 years; 68% 45,XO) and age-matched, normal girls. A total of 137 girls with Turner syndrome and 70 normal girls had lipid profile measurements, including cholesterol, high-density lipoprotein cholesterol, and triglycerides. Older girls with Turner syndrome (> 11.0 years) had increased cholesterol levels (p < 0.01), compared with control values (190 +/- 38 vs 165 +/- 26 mg/dl). Cholesterol levels were elevated in older subjects with Turner syndrome versus normal subjects, after adjustment for age, karyotype, and body mass index z score effects (p = 0.01). In the subjects with Turner syndrome but not the normal subjects, serum cholesterol values correlated with age, weight, and body mass index z score (p < 0.02). We conclude that adolescent girls with untreated Turner syndrome have significantly increased cholesterol levels, independent of age, body mass index z score, or karyotype, and that these precede any treatment with exogenous estrogen or growth hormone.