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Cardiovascular abnormalities in Turner's syndrome: What prevention?
Archives of Cardiovascular Disease (2008) 101, 485—490
Disponible en ligne sur www.sciencedirect.com
REVIEW
Cardiovascular abnormalities in Turner’s syndrome: What prevention? Anomalies cardiovasculaires du syndrome de Turner : quelle prevention ? Yves Dulac a,∗, Catherine Pienkowski b, Sylvia Abadir a, Maité Tauber b, Philippe Acar a a
Paediatric cardiology unit, Childrens’ Hospital, CHU Toulouse, 330, avenue de Grande-Bretagne, 31059 Toulouse cedex 9, France b Paediatric endocrinology unit, Childrens’ Hospital, CHU Toulouse, Toulouse cedex 9, France Received 8 February 2008; received in revised form 30 April 2008; accepted 8 May 2008 Available online 20 August 2008
KEYWORDS Turner; Coarctation of the aorta; Bicuspid aortic valve; Aortic dissection; Hypertension
∗
Summary Cardiovascular complications in Turner’s syndrome are the most common cause of excess early mortality, with a life expectancy that may be reduced by more than 10 years. Congenital cardiac abnormalities are described in approximately one third of patients. These abnormalities are mostly left heart obstructions, the most common of which are bicuspid aortic valve (16%) and coarctation of the aorta (11%). Dilatations of the ascending aorta are often described and may occur in isolation from any heart disease, suggesting a vasculopathy specific to the syndrome, probably predisposed to by extracardiac risk factors such as oestrogen deficiency, diabetes, dysplidaemia and overweight. The most feared complication is aortic dissection with around a 100 cases, described at average age of approximately 35-years-old. This is believed to complicate 2% of induced pregnancies. Hypertension (HBP) usually essential, affects up to 50% of patients with Turner’s syndrome. This is an important risk factor for cardiovascular complications and justifies aggressive treatment. On the other hand, retrospective studies have not demonstrated adverse cardiological effects due to growth hormone treatments. Patients with Turner’s syndrome merit regular cardiology follow-up from childhood onwards, particularly if they have treated heart disease. The merits of preventative treatments for aortic dilatation have not been demonstrated in Turner’s syndrome and justify prospective trials. © 2008 Published by Elsevier Masson SAS.
Corresponding author. E-mail address: [email protected] (Y. Dulac).
1875-2136/$ — see front matter © 2008 Published by Elsevier Masson SAS. doi:10.1016/j.acvd.2008.05.007
486
MOTS CLÉS Turner ; Coarctation aortique ; Bicuspidie aortique ; Dissection aortique ; Hypertension artérielle
Y. Dulac et al.
Résumé Dans le syndrome de Turner, les complications cardiovasculaires sont les principales responsables d’une surmortalité précoce avec une espérance de vie qui pourrait être réduite de plus de dix ans. Des anomalies cardiaques congénitales sont décrites chez environ un tiers des patientes. Ces cardiopathies sont essentiellement des obstacles du cœur gauche dont les plus fréquents sont la bicuspidie aortique (16 %) et la coarctation aortique (11 %). Des dilatations de l’aorte ascendante sont fréquemment décrites, y compris en l’absence de cardiopathie, faisant évoquer une vasculopathie propre au syndrome probablement favorisée par des facteurs de risque extracardiaques tels que : la carence en estrogène, le diabète, une dyslipidémie, une surcharge pondérale. La dissection aortique en est la complication la plus redoutable avec près d’une centaine de cas décrits à un âge moyen proche de 35 ans. Elle compliquerait 2 % des grossesses induites. L’hypertension artérielle (HTA), le plus souvent essentielle concerne jusqu’à 50 % des patientes avec syndrome de Turner. C’est un facteur de risque important de complications cardiovasculaires qui justifie un traitement rigoureux. En revanche, les études rétrospectives n’ont pas montré d’effets délétères cardiologiques des traitements par hormone de croissance. Les patientes avec syndrome de Turner justifient une surveillance cardiologique régulière dès l’enfance, notamment en cas de cardiopathie traitée. L’intérêt de traitements préventifs de la dilatation aortique n’a pas été démontré dans le syndrome de Turner et justifierait des études prospectives. © 2008 Published by Elsevier Masson SAS.
Introduction
tive surgery being offered depending on the extent of the left—right shunt [9,10].
Turner’s syndrome, which has a prevalence at birth of 1/2500 girls, is due to complete or partial absence of an X chromosome and is almost invariably associated with growth retardation and ovarian failure with infertility. Height prognosis is improved by growth hormone treatments. Pregnancies can occasionally be considered either spontaneously, particularly in mosaics, or after assisted medical conception (oocyte donation) in patients without appropriately monitored complications. Cardiovascular complications are those which are mostly responsible for early excess mortality and the life expectancy may be reduced by more than 10 years [1].
Antenatal diagnosis
Cardiovascular abnormalities and Turner’s syndrome
The antenatal diagnosis of Turner’s syndrome is suggested as a result of ultrasound abnormalities: mostly cystic hygroma or even anasarca, with a high incidence of congenital heart disease (60%) and spontaneous early fetal death [11—13]. The association between fetal jugular lymphatic obstruction responsible for cystic hygroma and congenital heart disease, particularly of the left side, has been established [14]. Haplo-insufficiency of genes not yet isolated and associated with ‘‘X’’ in the pseudo-autosomal region primary Xp involved in vascular morphogenesis may also explain the vascular and lymphatic abnormalities [15,16]. The congenital heart diseases found in utero are mostly coarctations of the aorta (45%) or hypoplastic left heart (13%). These have a poor prognosis and most result in medical termination of pregnancy or spontaneous fetal death [11].
Congenital heart disease
Left side obstructive abnormalities
Congenital cardiac abnormalities are described in approximately 30% of cases (23 to 45%) [2—4]. These are more common in series in which the cardiology assessment used a combination of echocardiography and magnetic resonance imaging (MRI). This technique demonstrates abnormalities, the clinical significance of which remains to be established [5—7]. The incidence is higher in 45 X monosomies and rarer (20%) in mosaics or in people with a structural X abnormality. The main cardiac abnormalities are left heart obstructions, the most common of which are bicuspid aortic valve (16%) and coarctation of the aorta (11%). These two anomalies may be combined [8]. Aortic valve dysplasia without a bicuspid valve and mitral valve abnormalities (ballooning, ‘‘parachute valve’’) are also found. Pulmonary and systemic (persistent superior vena cava) venous return abnormalities were seen in 13% of cases in an MRI study. Pulmonary venous return abnormalities, which are estimated to have a prevalence of approximately 3%, may be haemodynamically significant and result in correc-
Postnatally, left heart hypoplasia only therefore affects 2% of children with Turner’s syndrome. The only study that examined the prognosis of the Norwood procedure in this population showed a very poor prognosis: 15% survival at five years compared to 60% in non-syndromic patients [17]. When coarctation of the aorta is not suspected during pregnancy from ventricular asymmetry, it is usually diagnosed clinically in the first weeks of life. In some cases however it is diagnosed later in older children or adults by echocardiography or even MRI or aortic CT angiography. These investigations can detect unusual angulations or elongations of the aortic arch without repercussions affecting up to 50% of patients with Turner’s syndrome, although these have not been shown to increase the risk of aortic dissection [6]. Treatment is usually surgical if the obstruction is significant (more than 50%) and the patient is hypertensive and usually has very good postoperative results, morbidity mostly being due to the frequency of postoperative hypertension. Percutaneous angioplasty with or without stenting has been performed in native coarcta-
Cardiovascular abnormalities in Turner’s syndrome: What prevention? tions or recoarctations, with encouraging preliminary results [17]. Nevertheless a recent clinical case describes fatal dissection of the descending aorta after stenting in a young 19-years-old Turner’s woman [18]. An aortic valve abnormality, usually bicuspid valve, may be isolated and silent and only detected by echocardiography or even MRI. The features of aortic bicuspid valve and its risks of progression are similar in syndromic patients to the overall population. If discovered, patients should be treated to prevent risks of endocarditis with antibiotic prophylaxis for at risk procedures (dental care, surgical procedures). Regular follow-up will detect the development of complications: aortic stenosis and/or insufficiency, aortic dilatation and prevent the risks of dissection.
Acquired aortic abnormalities Aortic dilatation Aortic dilatation mostly affects the aortic root and ascending aorta. As proposed for Marfan’s syndrome, ascending aorta measurements are performed following the Roman recommendations on a left long axis parasternal view in end-diastole and assessed as a function of age and body surface area [19]. Nevertheless, the very definition of a dilated aorta raises a problem in this population in the absence of standard values appropriate for small patient height. The 95th percentile dimensions of the ascending aorta, i.e. 20 mm/m2 equivalent to values between 28 and 32 mm at the sinus of Valsalva, are abnormal in 24 to 42% of adult patients, far more than the 6.5% prevalence of aortic dilatation reported in the Lin study [6,7,20—23]. The ratio of ascending/descending aorta diameters which has the advantage of being unrelated to body surface area, is abnormal, i.e. more than 1,5 in one thirds of the patients with no history of coarctation. Dilatation is found primarily in patients with HBP and or bicuspid aortic valve or a past history of coarctation of the aorta, although may be found in the absence of any cardiological abnormalities. Arterial dilatations may extend to more distal vessels such as the carotid and brachial arteries [23]. Finally, carotid intimamedial thickening and defective aortic distensibility without endothelial dysfunction has been reported in recent studies [24]. Similar histological abnormalities have been found in Marfan’s syndrome and bicuspid aortic valve, involving cystic medial necrosis reported in 65% of dissected aortic tissue [23]. The similar vascular damage suggests possible involvement of the TGF- signalling pathway in the pathophysiology of arterial disease in Turner’s syndrome, as in Marfan’s syndrome or the Loeys Dietz syndrome [25,26]. The valve disease is predisposed to by extracardiac risk factors such as oestrogen deficiency, diabetes, dyslipidemia, overweight and hypothyroidism if these are not controlled [22,27].
Aortic dissection Acquired and potentially severe cardiovascular complications explain the poorer median survival than in the general population (70-years-old) with the excess cardiovascular mortality responsible for almost half of deaths. The relative risk of coronary artery disease was increased by a factor of 2.1, that of cerebrovascular disease by 2.7 in one epidemiological study [27]. Aortic dissection usually preceded by dilatation or aortic aneurysm is the most feared com-
487
plication as it is fatal in the acute phase in 75% of cases. It is responsible for 2 to 8% of deaths depending on the series [28—30] and was estimated to have an incidence of 36/100,000 Turner’s syndrome patients per year in a Danish series, occurring at an average age of 35-years-old, compared to 68-years-old in non-syndromic women [28]. Eighty-seven cases have been published in the last 45 years [29]. Unlike the knowledge obtained in Marfan’s syndrome the relationship between aortic dilatation and aortic dissection is inadequately documented in Turner’s syndrome: aortic dissections (3/166) have only been seen at values of 25 mm/m2 and above, i.e. more than 37 mm in the Matura series [15]. On the other hand Carlson describes two cases, one of which was 18-years-old, with aortic diameters less than 28.5 mm, i.e. below the 95th percentile. Risk factors are found in 90% of cases: left heart disease + HBP (40%), left heart disease without HBP (35%) and HBP alone (15%) [29]. This justifies aggressive anti-hypertensive management in these patents as it is the most commonly associated modifiable risk factor [21]. Around twenty cases of aortic dissection in non-hypertensive patients without congenital heart disease (9.5—61-years-old) has been described, providing evidence for the role of specific vasculopathy. Finally, aortic dissection is believed to complicate up to 2% of pregnancies in Turner’s syndrome implying careful selection of potential candidates for medically assisted conception as described further on [31].
Hypertension Hypertension affects up to 25% of adolescents with Turner’s syndrome and a higher percentage (40 to 60%) of adults: [21,27,32,33]. It is usually essential, although a renal or cardiological abnormality, which is present in 20% of cases, must be excluded [21,34]. It mostly affects systolic pressure, which does not fall at night. Its mechanism has not been clearly identified: an increase in plasma renin activity has been found in 50% of cases by some authors [34]. Abnormal vagosympathetic tone explaining relative tachycardia has recently been described [35]. Screening and follow-up are performed using blood pressure Holter (ABPM). Confirmed hypertension is an important risk factor for cardiovascular complications and justifies antihypertensive treatment with the aim of restoring blood pressure values strictly to normal. Beta-blockers, which have been shown to be useful in preventing cardiovascular complications in Marfan’s syndrome, the CEI or ARA 2 should be preferred. Calcium inhibitors may increase the risk of lymphodoema in these patients.
Electrical abnormalities Electrocardiographical abnormalities involving conduction or repolarisation defects have been described and attributed to neuro-autonomic dysfunction. Prolongation of the QT interval, usually moderate, has been reported from paediatric ages onwards. Nevertheless, no severe ventricular dysrhythmias have yet been documented [36]. An electrocardiogram (ECG) must be included as part of the follow-up investigations in these patients. The practical approach to patients with long QT interval is the same as that recommended in the general population.
488
Growth hormone and the heart in Turner’s syndrome Retrospective studies have not shown growth hormone treatment to have any adverse cardiological effect either on ventricular or aortic dimensions, the risk of dissection or on electrical abnormalities [37,38]. It may even have beneficial effects on the mechanical properties of the arterial wall, particularly distensibility [39].
Cardiovascular follow-up Methods [8,40] A cardiology assessment with a cardiologist skilled in congenital heart disease should be performed as soon as the diagnosis is made. This involves a clinical examination with examination of the peripheral pulses, measurement of blood pressures in all four limbs, an electrocardiogram ECG and echocardiogram. Echocardiography is used to investigate for congenital heart diseases, particularly those affecting the left heart: bicuspid aortic valve, aortic obstruction and venous return abnormalities. Ascending aorta measurements should be performed in a standardised and reproducible manner as in Marfan’s syndrome, at four levels on a long axis left parasternal end-diastolic view: aortic ring, sinus of Valsalva, sinotubular junction and ascending aorta 10 mm above the sinus of Valsalva. Aortic diameters should be compared against standard values defines as a function of body surface area by Roman in the absence of height-adjusted reference values for these patients [19]. MRI is recommended if the entire thoracic aorta cannot be sufficiently visualised, particularly in adults or adolescents, before a possible pregnancy, and if the patient has a past history of bicuspid aortic valve and/or surgically treated coarctation. In particular this can confirm the maximum dimensions of a dilated aorta and provide further information about the indication for surgery [39].
Follow-up intervals If the patient has a past history of surgically treated coarctation of the aorta, bicuspid aortic valve and/or hypertension, annual follow-up is recommended with measurement of blood pressure (possibly supplemented by ABPM), ECG and echocardiography. An MRI can be performed every three to five years depending on the cardiologist’s opinion. If clinically significant advancing aortic dilatation is present, a bi-annual cardiology review is recommended. In the absence of bicuspid aortic valve, past history of coarctation or hypertension, clinical follow-up with annual blood pressure measurement is recommended. A cardiology assessment with ECG, echocardiography and/or MRI can be offered every five years in the transition to adulthood and before any intended pregnancy.
Preventative management Risk factors Control of cardiovascular risk factors due to the syndrome is recommended from childhood onwards: treatment
Y. Dulac et al. of hypertension, diabetes, dyslipidaemia, management of overweight and sedentary lifestyle [40—44], etc. Patients with heart disease should be reminded regularly of the need for endocarditis prophylaxis for any at risk procedure.
Aortic dilatations In the absence of hypertension the utility of preventative beta-blocker treatment as recommended for Marfan’s syndrome at least when moderate dilatation of the ascending aorta is present has not been demonstrated [45]. Similarly, the use of sartans, which have been shown to have benefit in inhibiting the TGF signalling pathway in a mouse model with Marfan’s syndrome, needs to be confirmed in patients with Turner’s syndrome [26]. The level of maximum dilatation which justifies preventative replacement surgery to the ascending aorta has not been established in this population. It does however appear reasonable to consider the type of medical/surgical management at values over 25 mm/m2 body surface area or an increase in aortic diameter more than 10% per year [15]. Controlled prospective studies are therefore needed to provide information about the indications for more aggressive management of these patients [17].
Cardiology follow-up and pregnancy Spontaneous or medically assisted pregnancy carry a high cardiological risk because of the increased risk of aortic dilatation and therefore dissection. The United States survey of 146 patients with Turner’s syndrome treated by oocyte donation showed no deaths in 101 pregnancies and a single death due to aortic dissection in one patient awaiting the procedure. In the same country over the same period, four deaths were reported in Turner’s syndrome patients during pregnancy [31]. The risk of death in pregnancy appears to be increased by more than 100 times. A past history of aortic dissection, aortic dilatation or even bicuspid aortic valve are relative contra-indications to any pregnancy [46]. A cardiology assessment with echocardiography or even MRI if the echocardiogram is insufficient is therefore a prerequisite to any planned pregnancy. Pregnant patients should be followed up in a level 3 maternity unit with maternal ultrasound in the first and second trimesters and monthly in the third trimester. A cardiology review should be performed in the 15 days after delivery.
Conclusion Congenital or acquired cardiological problems occur commonly in Turner’s syndrome. They are potentially progressive and are responsible for severe complications, particularly a risk of aortic dissection in young women. They justify aggressive preventative management from childhood onwards, with regular cardiology assessments even in the absence of congenital heart disease, and control of risk factors, particularly HBP. Prospective studies are required to provide more information about the utility of treatments liable to prevent or delay aortic dilatation such as the beta-blockers or sartans in Turner’s syndrome.
Cardiovascular abnormalities in Turner’s syndrome: What prevention?
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[21] Elsheikh M, Casadei B, Conway GS, Wass JA. Hypertension is a major risk factor for aortic root dilatation in women with Turner’s syndrome. Clin Endocrinol 2001;54:69—73. [22] Baguet JP, Douchin S, Pierre H, Rossignol AM, Bost M, Mallion JM. Structural and functional abnormalities of large arteries in Turner’s syndrome. Heart 2005;91:1442—6. [23] Lin AE, Lippe B, Rosenfeld RG. Further delineation of aortic dilation, dissection, and rupture in patients with Turner’s syndrome. Pediatrics 1998;102:E12. [24] Ostberg JE, Donald AE, Halcox JPJ, Storry C, McCarthy C, Conway GS. Vasculopathy in Turner’s syndrome: arterial dilatation and intimal thickening without endothelial dysfunction. J Clin Endocrinol Metab 2005;90:5161—6. [25] Loeys BL, Schwarze U, Holm T, et al. Aneuvrysm syndromes caused by mutations in the TGFb receptor. N Engl J Med 2006;355:788—98. [26] Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents artic aneuvrysm model of Marfan syndrome. Science 2006;312:117—21. [27] Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner’s syndrome. J Clin Epidemiol 1998;51:147—58. [28] Gravholt CH, Landin-Wilhelmsen K, Stochholm K, et al. Clinical and epidemiological description of aortic dissection in Turner’s syndrome. Cardiol Young 2006;16:430—6. [29] Carlson M. Silberbach M. dissection of the aorta in Turner’s syndrome: two cases and review of 85 cases in the literature. J Med Genet 2007;44:745—9. [30] Sybert VP. Cardiovascular malformations and complications in Turner’s syndrome. Pediatrics 1998;101:E11. [31] Karnis MF, Zimon AE, Lalwani SI, Timmreck LS, Klipstein S, Reindollar RH. Risk of death in pregnancy achieved through ovocyte donation in patients with Turner’s syndrome: a national survey. Fertil Steril 2003;80:498—501. [32] Nathwani NC, Unwin R, Brook CG, Hindmarsh PC. Blood pressure and Turner’s syndrome. Clin Endocrinol 2000;52:363—70. [33] Gravholt CH, Hjerrild B. Hypertension and ischemic cardiovascular disease in Turner’s syndrome. International congress series 2006;1298:174—9. [34] Nathwani NC, Unwin R, Brook CG, Hindmarsh PC. The influence of renal and cardiovascular abnormalities on blood pressure in Turner’s syndrome. Clin Endocrinol 2000;52:371—7. [35] Gravholt CH, Hansen KW, Erlandsen M, Ebbehoj E, Christiansen JS. Nocturnal hypertension and impaired sympathovagal tone in Turner’s syndrome. J Hypertens 2006;24:353—60. [36] Bondy CA, Ceniceros I, Van PL, Bakalov VK, Rosing DR. Prolonged rate-corrected QT interval and other electrocardiogram abnormalities in girls with Turner’s syndrome. Pediatrics 2006;118:1220—5. [37] Radetti G, Crepaz R, Milanesi O, et al. Cardiac performance in Turner’s syndrome patients on growth hormone therapy. Horm Res 2001;55:240—4. [38] Bondy CA, Van PL, Bakalov VK, Ho VB. Growth hormone treatment and aortic dimensions in Turner’s syndrome. J Clin Endocrinol Metab 2006;91:1785—8. [39] Van den Berg J, Bannink EM, Wielopolski PA, et al. Aortic distensibility and dimensions and the effects of growth hormone treatment in the Turner’s syndrome. Am J Cardiol 2006;97:1644. [40] Haute Autorité de santé. PNDS syndrome de Turner. SaintDenis-La-Plaine. France : HAS 2008. [41] Ilyas M, Chu C, Ettles D, Mathew V, Atkin S. Evaluation by magnetic resonance imaging of aortic dilatation and coarctation in adult Turner’s syndrome patients. Clin Endocrinol 2006;65:154—7. [42] Gravholt CH, Naeraa RW, Nyholm B, et al. Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner’s syndrome. The impact of sex hormone replacement. Diabetes Care 1998;21:1062—70.
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Disponible en ligne sur www.sciencedirect.com
REVIEW
Cardiovascular abnormalities in Turner’s syndrome: What prevention? Anomalies cardiovasculaires du syndrome de Turner : quelle prevention ? Yves Dulac a,∗, Catherine Pienkowski b, Sylvia Abadir a, Maité Tauber b, Philippe Acar a a
Paediatric cardiology unit, Childrens’ Hospital, CHU Toulouse, 330, avenue de Grande-Bretagne, 31059 Toulouse cedex 9, France b Paediatric endocrinology unit, Childrens’ Hospital, CHU Toulouse, Toulouse cedex 9, France Received 8 February 2008; received in revised form 30 April 2008; accepted 8 May 2008 Available online 20 August 2008
KEYWORDS Turner; Coarctation of the aorta; Bicuspid aortic valve; Aortic dissection; Hypertension
∗
Summary Cardiovascular complications in Turner’s syndrome are the most common cause of excess early mortality, with a life expectancy that may be reduced by more than 10 years. Congenital cardiac abnormalities are described in approximately one third of patients. These abnormalities are mostly left heart obstructions, the most common of which are bicuspid aortic valve (16%) and coarctation of the aorta (11%). Dilatations of the ascending aorta are often described and may occur in isolation from any heart disease, suggesting a vasculopathy specific to the syndrome, probably predisposed to by extracardiac risk factors such as oestrogen deficiency, diabetes, dysplidaemia and overweight. The most feared complication is aortic dissection with around a 100 cases, described at average age of approximately 35-years-old. This is believed to complicate 2% of induced pregnancies. Hypertension (HBP) usually essential, affects up to 50% of patients with Turner’s syndrome. This is an important risk factor for cardiovascular complications and justifies aggressive treatment. On the other hand, retrospective studies have not demonstrated adverse cardiological effects due to growth hormone treatments. Patients with Turner’s syndrome merit regular cardiology follow-up from childhood onwards, particularly if they have treated heart disease. The merits of preventative treatments for aortic dilatation have not been demonstrated in Turner’s syndrome and justify prospective trials. © 2008 Published by Elsevier Masson SAS.
Corresponding author. E-mail address: [email protected] (Y. Dulac).
1875-2136/$ — see front matter © 2008 Published by Elsevier Masson SAS. doi:10.1016/j.acvd.2008.05.007
486
MOTS CLÉS Turner ; Coarctation aortique ; Bicuspidie aortique ; Dissection aortique ; Hypertension artérielle
Y. Dulac et al.
Résumé Dans le syndrome de Turner, les complications cardiovasculaires sont les principales responsables d’une surmortalité précoce avec une espérance de vie qui pourrait être réduite de plus de dix ans. Des anomalies cardiaques congénitales sont décrites chez environ un tiers des patientes. Ces cardiopathies sont essentiellement des obstacles du cœur gauche dont les plus fréquents sont la bicuspidie aortique (16 %) et la coarctation aortique (11 %). Des dilatations de l’aorte ascendante sont fréquemment décrites, y compris en l’absence de cardiopathie, faisant évoquer une vasculopathie propre au syndrome probablement favorisée par des facteurs de risque extracardiaques tels que : la carence en estrogène, le diabète, une dyslipidémie, une surcharge pondérale. La dissection aortique en est la complication la plus redoutable avec près d’une centaine de cas décrits à un âge moyen proche de 35 ans. Elle compliquerait 2 % des grossesses induites. L’hypertension artérielle (HTA), le plus souvent essentielle concerne jusqu’à 50 % des patientes avec syndrome de Turner. C’est un facteur de risque important de complications cardiovasculaires qui justifie un traitement rigoureux. En revanche, les études rétrospectives n’ont pas montré d’effets délétères cardiologiques des traitements par hormone de croissance. Les patientes avec syndrome de Turner justifient une surveillance cardiologique régulière dès l’enfance, notamment en cas de cardiopathie traitée. L’intérêt de traitements préventifs de la dilatation aortique n’a pas été démontré dans le syndrome de Turner et justifierait des études prospectives. © 2008 Published by Elsevier Masson SAS.
Introduction
tive surgery being offered depending on the extent of the left—right shunt [9,10].
Turner’s syndrome, which has a prevalence at birth of 1/2500 girls, is due to complete or partial absence of an X chromosome and is almost invariably associated with growth retardation and ovarian failure with infertility. Height prognosis is improved by growth hormone treatments. Pregnancies can occasionally be considered either spontaneously, particularly in mosaics, or after assisted medical conception (oocyte donation) in patients without appropriately monitored complications. Cardiovascular complications are those which are mostly responsible for early excess mortality and the life expectancy may be reduced by more than 10 years [1].
Antenatal diagnosis
Cardiovascular abnormalities and Turner’s syndrome
The antenatal diagnosis of Turner’s syndrome is suggested as a result of ultrasound abnormalities: mostly cystic hygroma or even anasarca, with a high incidence of congenital heart disease (60%) and spontaneous early fetal death [11—13]. The association between fetal jugular lymphatic obstruction responsible for cystic hygroma and congenital heart disease, particularly of the left side, has been established [14]. Haplo-insufficiency of genes not yet isolated and associated with ‘‘X’’ in the pseudo-autosomal region primary Xp involved in vascular morphogenesis may also explain the vascular and lymphatic abnormalities [15,16]. The congenital heart diseases found in utero are mostly coarctations of the aorta (45%) or hypoplastic left heart (13%). These have a poor prognosis and most result in medical termination of pregnancy or spontaneous fetal death [11].
Congenital heart disease
Left side obstructive abnormalities
Congenital cardiac abnormalities are described in approximately 30% of cases (23 to 45%) [2—4]. These are more common in series in which the cardiology assessment used a combination of echocardiography and magnetic resonance imaging (MRI). This technique demonstrates abnormalities, the clinical significance of which remains to be established [5—7]. The incidence is higher in 45 X monosomies and rarer (20%) in mosaics or in people with a structural X abnormality. The main cardiac abnormalities are left heart obstructions, the most common of which are bicuspid aortic valve (16%) and coarctation of the aorta (11%). These two anomalies may be combined [8]. Aortic valve dysplasia without a bicuspid valve and mitral valve abnormalities (ballooning, ‘‘parachute valve’’) are also found. Pulmonary and systemic (persistent superior vena cava) venous return abnormalities were seen in 13% of cases in an MRI study. Pulmonary venous return abnormalities, which are estimated to have a prevalence of approximately 3%, may be haemodynamically significant and result in correc-
Postnatally, left heart hypoplasia only therefore affects 2% of children with Turner’s syndrome. The only study that examined the prognosis of the Norwood procedure in this population showed a very poor prognosis: 15% survival at five years compared to 60% in non-syndromic patients [17]. When coarctation of the aorta is not suspected during pregnancy from ventricular asymmetry, it is usually diagnosed clinically in the first weeks of life. In some cases however it is diagnosed later in older children or adults by echocardiography or even MRI or aortic CT angiography. These investigations can detect unusual angulations or elongations of the aortic arch without repercussions affecting up to 50% of patients with Turner’s syndrome, although these have not been shown to increase the risk of aortic dissection [6]. Treatment is usually surgical if the obstruction is significant (more than 50%) and the patient is hypertensive and usually has very good postoperative results, morbidity mostly being due to the frequency of postoperative hypertension. Percutaneous angioplasty with or without stenting has been performed in native coarcta-
Cardiovascular abnormalities in Turner’s syndrome: What prevention? tions or recoarctations, with encouraging preliminary results [17]. Nevertheless a recent clinical case describes fatal dissection of the descending aorta after stenting in a young 19-years-old Turner’s woman [18]. An aortic valve abnormality, usually bicuspid valve, may be isolated and silent and only detected by echocardiography or even MRI. The features of aortic bicuspid valve and its risks of progression are similar in syndromic patients to the overall population. If discovered, patients should be treated to prevent risks of endocarditis with antibiotic prophylaxis for at risk procedures (dental care, surgical procedures). Regular follow-up will detect the development of complications: aortic stenosis and/or insufficiency, aortic dilatation and prevent the risks of dissection.
Acquired aortic abnormalities Aortic dilatation Aortic dilatation mostly affects the aortic root and ascending aorta. As proposed for Marfan’s syndrome, ascending aorta measurements are performed following the Roman recommendations on a left long axis parasternal view in end-diastole and assessed as a function of age and body surface area [19]. Nevertheless, the very definition of a dilated aorta raises a problem in this population in the absence of standard values appropriate for small patient height. The 95th percentile dimensions of the ascending aorta, i.e. 20 mm/m2 equivalent to values between 28 and 32 mm at the sinus of Valsalva, are abnormal in 24 to 42% of adult patients, far more than the 6.5% prevalence of aortic dilatation reported in the Lin study [6,7,20—23]. The ratio of ascending/descending aorta diameters which has the advantage of being unrelated to body surface area, is abnormal, i.e. more than 1,5 in one thirds of the patients with no history of coarctation. Dilatation is found primarily in patients with HBP and or bicuspid aortic valve or a past history of coarctation of the aorta, although may be found in the absence of any cardiological abnormalities. Arterial dilatations may extend to more distal vessels such as the carotid and brachial arteries [23]. Finally, carotid intimamedial thickening and defective aortic distensibility without endothelial dysfunction has been reported in recent studies [24]. Similar histological abnormalities have been found in Marfan’s syndrome and bicuspid aortic valve, involving cystic medial necrosis reported in 65% of dissected aortic tissue [23]. The similar vascular damage suggests possible involvement of the TGF- signalling pathway in the pathophysiology of arterial disease in Turner’s syndrome, as in Marfan’s syndrome or the Loeys Dietz syndrome [25,26]. The valve disease is predisposed to by extracardiac risk factors such as oestrogen deficiency, diabetes, dyslipidemia, overweight and hypothyroidism if these are not controlled [22,27].
Aortic dissection Acquired and potentially severe cardiovascular complications explain the poorer median survival than in the general population (70-years-old) with the excess cardiovascular mortality responsible for almost half of deaths. The relative risk of coronary artery disease was increased by a factor of 2.1, that of cerebrovascular disease by 2.7 in one epidemiological study [27]. Aortic dissection usually preceded by dilatation or aortic aneurysm is the most feared com-
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plication as it is fatal in the acute phase in 75% of cases. It is responsible for 2 to 8% of deaths depending on the series [28—30] and was estimated to have an incidence of 36/100,000 Turner’s syndrome patients per year in a Danish series, occurring at an average age of 35-years-old, compared to 68-years-old in non-syndromic women [28]. Eighty-seven cases have been published in the last 45 years [29]. Unlike the knowledge obtained in Marfan’s syndrome the relationship between aortic dilatation and aortic dissection is inadequately documented in Turner’s syndrome: aortic dissections (3/166) have only been seen at values of 25 mm/m2 and above, i.e. more than 37 mm in the Matura series [15]. On the other hand Carlson describes two cases, one of which was 18-years-old, with aortic diameters less than 28.5 mm, i.e. below the 95th percentile. Risk factors are found in 90% of cases: left heart disease + HBP (40%), left heart disease without HBP (35%) and HBP alone (15%) [29]. This justifies aggressive anti-hypertensive management in these patents as it is the most commonly associated modifiable risk factor [21]. Around twenty cases of aortic dissection in non-hypertensive patients without congenital heart disease (9.5—61-years-old) has been described, providing evidence for the role of specific vasculopathy. Finally, aortic dissection is believed to complicate up to 2% of pregnancies in Turner’s syndrome implying careful selection of potential candidates for medically assisted conception as described further on [31].
Hypertension Hypertension affects up to 25% of adolescents with Turner’s syndrome and a higher percentage (40 to 60%) of adults: [21,27,32,33]. It is usually essential, although a renal or cardiological abnormality, which is present in 20% of cases, must be excluded [21,34]. It mostly affects systolic pressure, which does not fall at night. Its mechanism has not been clearly identified: an increase in plasma renin activity has been found in 50% of cases by some authors [34]. Abnormal vagosympathetic tone explaining relative tachycardia has recently been described [35]. Screening and follow-up are performed using blood pressure Holter (ABPM). Confirmed hypertension is an important risk factor for cardiovascular complications and justifies antihypertensive treatment with the aim of restoring blood pressure values strictly to normal. Beta-blockers, which have been shown to be useful in preventing cardiovascular complications in Marfan’s syndrome, the CEI or ARA 2 should be preferred. Calcium inhibitors may increase the risk of lymphodoema in these patients.
Electrical abnormalities Electrocardiographical abnormalities involving conduction or repolarisation defects have been described and attributed to neuro-autonomic dysfunction. Prolongation of the QT interval, usually moderate, has been reported from paediatric ages onwards. Nevertheless, no severe ventricular dysrhythmias have yet been documented [36]. An electrocardiogram (ECG) must be included as part of the follow-up investigations in these patients. The practical approach to patients with long QT interval is the same as that recommended in the general population.
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Growth hormone and the heart in Turner’s syndrome Retrospective studies have not shown growth hormone treatment to have any adverse cardiological effect either on ventricular or aortic dimensions, the risk of dissection or on electrical abnormalities [37,38]. It may even have beneficial effects on the mechanical properties of the arterial wall, particularly distensibility [39].
Cardiovascular follow-up Methods [8,40] A cardiology assessment with a cardiologist skilled in congenital heart disease should be performed as soon as the diagnosis is made. This involves a clinical examination with examination of the peripheral pulses, measurement of blood pressures in all four limbs, an electrocardiogram ECG and echocardiogram. Echocardiography is used to investigate for congenital heart diseases, particularly those affecting the left heart: bicuspid aortic valve, aortic obstruction and venous return abnormalities. Ascending aorta measurements should be performed in a standardised and reproducible manner as in Marfan’s syndrome, at four levels on a long axis left parasternal end-diastolic view: aortic ring, sinus of Valsalva, sinotubular junction and ascending aorta 10 mm above the sinus of Valsalva. Aortic diameters should be compared against standard values defines as a function of body surface area by Roman in the absence of height-adjusted reference values for these patients [19]. MRI is recommended if the entire thoracic aorta cannot be sufficiently visualised, particularly in adults or adolescents, before a possible pregnancy, and if the patient has a past history of bicuspid aortic valve and/or surgically treated coarctation. In particular this can confirm the maximum dimensions of a dilated aorta and provide further information about the indication for surgery [39].
Follow-up intervals If the patient has a past history of surgically treated coarctation of the aorta, bicuspid aortic valve and/or hypertension, annual follow-up is recommended with measurement of blood pressure (possibly supplemented by ABPM), ECG and echocardiography. An MRI can be performed every three to five years depending on the cardiologist’s opinion. If clinically significant advancing aortic dilatation is present, a bi-annual cardiology review is recommended. In the absence of bicuspid aortic valve, past history of coarctation or hypertension, clinical follow-up with annual blood pressure measurement is recommended. A cardiology assessment with ECG, echocardiography and/or MRI can be offered every five years in the transition to adulthood and before any intended pregnancy.
Preventative management Risk factors Control of cardiovascular risk factors due to the syndrome is recommended from childhood onwards: treatment
Y. Dulac et al. of hypertension, diabetes, dyslipidaemia, management of overweight and sedentary lifestyle [40—44], etc. Patients with heart disease should be reminded regularly of the need for endocarditis prophylaxis for any at risk procedure.
Aortic dilatations In the absence of hypertension the utility of preventative beta-blocker treatment as recommended for Marfan’s syndrome at least when moderate dilatation of the ascending aorta is present has not been demonstrated [45]. Similarly, the use of sartans, which have been shown to have benefit in inhibiting the TGF signalling pathway in a mouse model with Marfan’s syndrome, needs to be confirmed in patients with Turner’s syndrome [26]. The level of maximum dilatation which justifies preventative replacement surgery to the ascending aorta has not been established in this population. It does however appear reasonable to consider the type of medical/surgical management at values over 25 mm/m2 body surface area or an increase in aortic diameter more than 10% per year [15]. Controlled prospective studies are therefore needed to provide information about the indications for more aggressive management of these patients [17].
Cardiology follow-up and pregnancy Spontaneous or medically assisted pregnancy carry a high cardiological risk because of the increased risk of aortic dilatation and therefore dissection. The United States survey of 146 patients with Turner’s syndrome treated by oocyte donation showed no deaths in 101 pregnancies and a single death due to aortic dissection in one patient awaiting the procedure. In the same country over the same period, four deaths were reported in Turner’s syndrome patients during pregnancy [31]. The risk of death in pregnancy appears to be increased by more than 100 times. A past history of aortic dissection, aortic dilatation or even bicuspid aortic valve are relative contra-indications to any pregnancy [46]. A cardiology assessment with echocardiography or even MRI if the echocardiogram is insufficient is therefore a prerequisite to any planned pregnancy. Pregnant patients should be followed up in a level 3 maternity unit with maternal ultrasound in the first and second trimesters and monthly in the third trimester. A cardiology review should be performed in the 15 days after delivery.
Conclusion Congenital or acquired cardiological problems occur commonly in Turner’s syndrome. They are potentially progressive and are responsible for severe complications, particularly a risk of aortic dissection in young women. They justify aggressive preventative management from childhood onwards, with regular cardiology assessments even in the absence of congenital heart disease, and control of risk factors, particularly HBP. Prospective studies are required to provide more information about the utility of treatments liable to prevent or delay aortic dilatation such as the beta-blockers or sartans in Turner’s syndrome.
Cardiovascular abnormalities in Turner’s syndrome: What prevention?
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