Aortic dissection in children and adolescents with Turner syndrome: risk factors and management recommendations

Abstract

There is a general lack of awareness of the risk of aortic dissection in Turner syndrome (TS) from both patients with TS and their physicians. Patients often ignore symptoms for up to 24 h before seeking medical advice, significantly increasing their risk of death. A clinical profile of those at risk of dissection is emerging and includes the presence of congenital heart defects, aortic dilatation and hypertension. MRI has revolutionised the visualisation of cardiovascular anatomy in TS but remains underutilised, especially in children and adolescents, and there is currently little guidance on blood pressure (BP) assessment or hypertension management. Children and adolescents with TS at risk of dissection could be easily identified by timely imaging and BP assessment. This would allow medical management or surgical intervention to be put in place to reduce the risk of this major, and often fatal, complication. Since guidance is lacking, we have reviewed the literature on the risk factors for dissection in TS during childhood and adolescence, and make recommendations on the assessment and management of these patients.

Introduction

Aortic dissection is six times more common in Turner syndrome (TS) than in the general population, with an estimated incidence of 40 cases per 100 000 TS years. 1 It most commonly affects women in their mid-30s but can occur during childhood and adolescence. 2-4 The annual incidence of dissection in TS is 15 cases per 100 000 for children and adolescents, 78 cases per 100 000 for women 20-40 years, and 50 cases per 100 000 for older women with TS. 1 Typically, this complication is recognised late and is often fatal, accounting for 8% of all TS deaths. 5 A recent report from the International Turner Syndrome Aortic Dissection Registry has helped characterise the profile of women at risk of aortic dissection. 6 This voluntary registry retrospectively recruited 20 patients with TS with dissection, through the Turner Syndrome Society of the USA, following completion of a questionnaire by the survivors themselves or individuals aware of a dissection in a patient with TS. The most frequent associations were a bicuspid aortic valve, antecedent aortic dilatation and hypertension. In addition, a trend to delay seeking medical advice was seen in younger patients with TS, substantially reducing their likelihood of survival.

Earlier papers have also reported on aortic dissection in TS and these included children and adolescents. 2 3 One paper recorded 46 cases of dissection in patients with TS, 9 of whom were children or adolescents, and the youngest was 4 years of age. 2 In these younger patients, dissection was also strongly associated with the presence of congenital heart defects. 2 The documentation of blood pressure (BP) in these younger patients was generally poor, but studies show that hypertension is common in children and adolescents with TS. 7 8 In addition, one case report describes progressive aortic dilatation during childhood, eventually ending in dissection and rupture in adolescence. 4 However, routine screening for aortic dilatation during childhood and adolescence is not often performed. Since guidance is lacking, we have reviewed the literature on these key risk factors for aortic dissection, and propose recommendations on the optimal imaging for congenital heart defects and aortic dilatation, and on the assessment and management of BP in this patient group.

Risk factors for aortic dissection

Congenital heart defects

A bicuspid aortic valve occurs in 30% of patients with TS. 9 However, it was present in almost all of the registry patients (95%) who underwent dissection. 6 Hence, having a bicuspid aortic valve substantially increases the risk of dissection, and its identification is extremely important. Echocardiography has become the standard of care for screening and should be performed at diagnosis. However, even in children, echocardiographic visualisation can be poor. 9 If good views of the aortic valve are not obtained, cardiac MRI should be the next step because most aortic valves not clearly visualised by echocardiography in TS are abnormal. 9

Coarctation of the aorta affects 12% of patients with TS 10 11 and is present in 89% of children and adolescents who undergo dissection. 2 Some of these individuals have had a coarctation repair several years before dissection, but some occur immediately after corrective coarctation surgery, 2 resulting in death. Coarctation is usually diagnosed in infancy, often with congestive cardiac failure, if critical. Occasionally, it may be diagnosed later in childhood following the detection of hypertension or radiofemoral delay. When coarctation is suspected, an echocardiogram is the initial screening investigation, although imaging with MRI may be required in older children or adolescents if visualisation is difficult. 12

Hypertension

In TS, hypertension affects 25% children and adolescents, 7 often starting in mid-childhood and increasing with age, eventually affecting up to half of all adult women with TS. 13 In children and adolescents, normative BP percentiles are based on gender, age and height. 14 BP thresholds have been set out by the US National Institutes for Health, 'The Fourth Report on the Diagnosis, Evaluation, and Treatment of High BP in Children and Adolescents' 14 (outlined below in table 1 ). Generally, three BP measurements are obtained during each clinical encounter. If the average reading is >=95th centile and it was taken with an oscillometric device, then it requires confirmation by auscultation because the reference tables are based on auscultatory measurements. 14

Table 1

Definition	Systolic and/or diastolic BP
Normal	<90th centile
Pre-hypertension*	>=90th-<95th centile or >=120/80 mm Hg (even if <90th centile)[dagger]
Stage I hypertension	95th-99th centile plus 5 mm Hg
Stage II hypertension	>99th centile plus 5 mm Hg

*High normal BP.

[dagger]Adolescents only.

Ambulatory BP measurement is increasingly recognised as being indispensable to the diagnosis of hypertension. It is especially helpful in the evaluation of 'white coat' hypertension and non-dipping (loss of the normal night-time reduction in BP), both of which are known to affect children and adolescents with TS. 7 8 Non-dipping is predictive for future cardiovascular events and increases the risk of end organ damage. 15 Normative ambulatory BP data have been obtained for children, although in small numbers, and thresholds have been proposed. 16 At present, the evidence for home BP measurements in children and adolescents is limited, 16 but may in future prove to be a valuable alternative, as it is in adults.

Hypertension in TS may be due to undiagnosed coarctation or, in the context of repaired coarctation, it may be due to the resetting of the baroreceptors or constriction at the coarctation site. 12 Renal function tends to be normal despite a high incidence of renal tract abnormalities seen in TS 17 and therefore not felt to influence BP in TS. However, medications such as stimulants for the treatment of attention-deficit disorder 18 and oestrogen therapy may contribute to an increase in BP. Oral oestrogen replacement is most often used for pubertal induction but transdermal replacement may offer a more physiological alternative. 19 One study involving 18 hypogonadal woman compared the effects of physiological hormone replacement (transdermal oestradiol and vaginal progesterone), against standard hormone replacement(oral ethinylestradiol and norethisterone) on cardiovascular health (as measured by ambulatory BP monitoring), with each treatment given for 12 months. Importantly, the results showed that physiological replacement was associated with a significantly lower mean 24 h systolic and diastolic BP. Systolic BP was 7.3 mm Hg (95% CI 2.5 to 12.0 mm Hg) and diastolic 7.4 mm Hg (95% CI 3.9 to 11.0 mm Hg), lower at 12 months 20 -a major BP difference. However, the oestrogen dose for pubertal induction is much lower, and whether transdermal rather than standard oral replacement has a similar effect on BP during induction requires further study.

Aortic dilatation

Aortic dilatation affects 19% of children and adolescents with TS and can start from 6 years of age. 21 In the general population, predisposing factors for aortic dilatation are congenital heart defects and hypertension, both of which are commonly seen in TS. However, a small number of patients with TS with aortic dilatation have no apparent risk factors other than TS itself. 11 Dilatation of other major vessels in TS, including the brachial and carotid arteries, 22 has also been shown, giving rise to the theory that a large vessel vasculopathy is associated with TS.

Traditionally, echocardiography has been the mainstay of diagnosis for aortic dilatation in infants and children. Z-scores are calculated from measurements taken at the aortic valve, aortic sinus, sinotubular junction and proximal ascending aorta. These dimensions are adjusted to body surface area (BSA) and compared with reference values from a normal paediatric population. Dilatation is defined by a Z-score >=2. 23 However, echocardiography has been shown to have a much lower sensitivity for detecting aortic enlargement in TS than MRI, missing some cases in both children 21 and adults. 24 In addition, echocardiography may not allow adequate visualisation of the thoracic aorta, 25 especially in older children and adolescents. This complete evaluation is essential because dilatation may also affect the descending aorta, in which around 20% of TS dissections occur. 6

Thoracic MRI is the imaging modality of choice for aortic dimensions in older children and adolescents. Using MRI, the ascending and descending aortic diameters can be measured at the level of the right pulmonary artery, and then normalised to BSA to give the aortic size index (ASI), which has been proposed as a reliable criterion to predict risk of aortic dissection in women with TS. 26 Based on data taken from age-matched female controls, the 95th centile equates to an ASI >2.0 cm/m² , indicating clinical concern and a need for close monitoring. The 99th centile equates to an ASI >=2.5 cm/m² , which should trigger urgent evaluation for intervention. In addition, earlier MRI studies assessing aortic dilatation in children and adolescents with TS also defined aortic dilatation as >95th centile. 9 21

A recent study with MRI has shown that aortic dilatation in women with TS is progressive, and that this progression is accelerated in the presence of a bicuspid aortic valve. 27 Clearly, aortic size during childhood and adolescence will increase due to somatic growth, but longitudinal MRI studies of the ascending and descending aorta will be crucial in determining whether the rate of growth over time is pathological.

Recommendations

Cardiovascular assessment at diagnosis

All children and adolescents with TS should have a thorough clinical assessment for congenital heart defects at diagnosis by a cardiologist familiar with the spectrum of cardiovascular issues encountered in TS. 28 This should include BP measurement in the arms and legs, a baseline ECG and echocardiography. A raised upper limb BP, along with a weak or absent femoral pulse, radiofemoral delay or a BP >=20 mm Hg lower in the legs than in the arms 12 should raise concerns about coarctation of the aorta. Echocardiography should be performed in young children to confirm the clinical findings of coarctation, and should include an assessment of aortic diameter, although MRI may be required in older children and adolescents. 12 Screening for a bicuspid aortic valve should be performed in all patients at diagnosis and, if visualisation of the aortic valve is poor, cardiac MRI should be the next approach. An ECG should be performed at diagnosis to identify cardiac conduction defects, which are common in TS. 29

BP monitoring

It is extremely important that children and adolescents with TS and hypertension are identified early, and have their BP successfully lowered, because hypertension is a major risk factor for aortic dissection and rupture. 6 A BP measurement >=95th centile should be confirmed by ambulatory BP monitoring. Conducting ambulatory BP monitoring requires specific equipment and trained staff and should only be used by those with experience and knowledge of its interpretation. In addition, diagnostic ambulatory BP values are limited to children and adolescents >120 cm in height. If ambulatory BP monitoring is not available or the patient is too small, clinic BPs should be taken on three separate visits, over several weeks or months, before making a new diagnosis of hypertension. This is because high levels tend to fall on subsequent measurement, 14 and a diagnosis of hypertension has major health implications. An emerging alternative is home BP monitoring but there are limited normal data on children and adolescents. 16 It is gaining increasing prominence in the treatment of hypertension in adults and it certainly has a strong appeal for the evaluation of BP in girls with TS, as they are often very anxious at clinic and take time to become accustomed to BP assessments. If home BP monitoring were to be recommended by a physician, the family should be advised to purchase a British Hypertension Society validated BP monitor along with an appropriately sized cuff. 14 16

Hypertension: reducing cardiovascular risk factors

Box 1 Evaluation of comorbidity following confirmed hypertension Investigation Weight

Height

Urea, electrolytes and creatinine

Serum lipids and triglycerides

Fasting plasma glucose

Urinalysis plus albumin-creatinine ratio

Children and adolescents with TS have a predisposition to obesity and there is a strong correlation between weight and BP in children without TS. 31 The best way to define obesity in children is by body mass index (BMI) centiles, which are expressed in relation to an age-matched and sex-matched population. 32 By convention in the UK, the BMI centiles of the UK 1990 chart are used as the population reference standard. Children with a BMI >=91st centile are overweight, and those with a BMI >=98th centile are obese. For children or adolescents who are overweight or obese, weight maintenance is an acceptable goal, and allows a gradual decline in BMI over time. 32

Hypertension management: non-pharmacological intervention

The mainstay of hypertension management in children and adolescents with TS is non-pharmacological treatment. It is generally accepted that hypertensive individuals can benefit from a diet high in fruits and vegetables, regular meals, including a healthy breakfast, and reduction in foods with an excess of sugar and saturated fat. Salt restriction in children and adolescents has been associated with small reductions in BP, in the range 1-3 mm Hg. 14 Sedentary behaviours should be reduced to less than 2 h/day, and moderate exercise should be undertaken for at least 40 min, 3-5 days a week. 31 Smoke exposure, including secondhand smoke, increases the risk of cardiovascular disease and aortopathy, 33 so all children or adolescents, or their close contacts, who smoke should be counselled to quit.

Hypertension management: pharmacological intervention

If pharmacological agents are needed, we suggest starting with an angiotensin receptor blocker (ARB) at the lowest available dose. This is because targeting the cytokine transforming growth factor [beta] (TGF[beta]) with ARBs in patients with Marfan syndrome significantly slowed the rate of progressive aortic dilatation 34 and TGF[beta] has recently been shown to be elevated in bicuspid aortopathy. 35 However, this association is unproven in TS. Historically, [beta]-blockers have been first-line antihypertensive agents and in TS may be particularly appropriate because a resting tachycardia is a common clinical finding. 8 However, they have been relegated to fourth-line agents in the BHS guidelines for adult treatment because they increase the risk of glucose intolerance, 36 and type 2 diabetes is already common in adults with TS. 30 In addition, calcium channel blockers may cause peripheral oedema, and worsen lymphoedema, which is often present.

Target goals for BP

Since current evidence on BP management in TS is limited, we propose BP targets based on the presence of risk factors for dissection, which require more aggressive BP lowering (see algorithm).

Assessment of aortic dilatation

Current US guidance suggests that children and adolescents with TS should have a 'full evaluation with thoracic MRI at an age when it can be performed without sedation'. 28 One paper has shown this to be possible from 6 years of age 21 and also demonstrated dilatation in this patient. However, it would be our experience that performing MRI in children with TS at 6 years of age is difficult without general anesthesia. Therefore, we suggest that the initial evaluation of the aorta should be performed by echocardiography and, if adequate visualisation is not achieved or dimensions are abnormal, then imaging by thoracic MRI should be considered. If echocardiography evaluation of the aorta is normal, a full evaluation of the entire aorta by thoracic MRI should be performed at around 10 years of age. Thoracic MRI should be performed at a centre with appropriate technical expertise to screen and interpret these abnormalities. If the ASI is >=2.5 cm/m² , an urgent surgical opinion should be sought. If the ASI is >2 cm/m² , then dilatation is present, requiring BP to be managed appropriately along with annual MRI (or earlier if clinically indicated). If the ASI is <2 cm/m² but risk factors for dissection are present, the child or adolescent should be considered at moderate risk of dissection, and repeat MRI should be considered every 3 years in the first instance, to determine any change in aortic diameter. If no risk factors for dissection are present and no baseline dilatation is seen (ASI<2 cm/m² ), repeated imaging is warranted, given that dilatation can occur even in the absence of predisposing factors. In this instance, MRI should be repeated at transition (see algorithm). If aortic dimensions are stable over a period of time, the time between screening visits may be extended, although no evidence base currently exists for this recommendation.

Patient education

All doctors who care for children and adolescents with TS should be aware of the risk of aortic dissection and should appropriately convey this risk to patients and families, starting from childhood. A high pain threshold is well recognised in TS and might contribute to the delay in diagnosis. Therefore, patients should be advised to attend the emergency department early after experiencing sustained chest pain (>30 min), regardless of the severity of symptoms, because a late presentation with aortic dissection is invariably fatal.

Conclusions

In TS, careful clinical assessment for risk factors of aortic dissection, from diagnosis, is essential. Echocardiography should be performed at diagnosis with clear documentation of the morphology of the aortic valve, the presence of coarctation or a previous repair, and aortic diameters. Any findings of concern, such as indeterminate morphology of the aortic valve, or aortic dilatation, should be further evaluated with MRI. All children with TS should have regular clinic BP monitoring from 3 years of age. 14 If clinic BP readings are >=95th centile, they should be confirmed with ambulatory BP monitoring and, if hypertension is present, BP lowering with lifestyle changes and/or pharmacological treatment is required. All girls with TS should undergo routine thoracic MRI at 10 years of age. Any new findings on MRI should be noted, paying particular attention to aortic valve morphology and aortic diameters. Hereafter, the likelihood of dissection can be graded according to risk factors and helps to determine the interval between subsequent MRI. We suggest repeating thoracic MRI at timely intervals even in the absence of congenital heart defects or hypertension because aortic dilatation may still occur. However, it remains uncertain what degree of dilatation indicates a risk of impending dissection. Until larger prospective studies confirm that longer imaging intervals are safe, we propose that children and adolescents with TS should undergo regular and relatively frequent thoracic MRI.

Footnote

Contributors: ET prepared the manuscript. All co-authors have contributed equally to the critical revision and redrafting of the manuscript.

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

References

1 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. doi:10.1017/S1047951106000928

2 Sybert VP. Cardiovascular malformations and complications in Turner syndrome. Pediatrics 1998; 101: E11-17. doi:10.1542/peds.101.1.e11

3 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. doi:10.1136/jmg.2007.052019

4 Pleskacova J, Rucklova K, Popelova J, et al. Aortic dissection and rupture in a 16-year-old girl with Turner syndrome following previous progression of aortic dilatation. Eur J Pediatr 2010; 169: 1283-6. doi:10.1007/s00431-010-1197-4

5 Swerdlow AJ, Hermon C, Jacobs PA, et al. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001; 65: 177-88. doi:10.1046/j.1469-1809.2001.6520177.x

6 Carlson M, Airhart N, Lopez L, et al. 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. doi:10.1161/CIRCULATIONAHA.111.088633

7 Nathwani NC, Unwin R, Brook CGD, et al. Blood pressure and Turner syndrome. Clin Endocrinol 2000; 52: 363-70. doi:10.1046/j.1365-2265.2000.00960.x

8 Gravholt CH, Hansen KW, Erlandsen M, et al. Nocturnal hypertension and impaired sympathovagal tone in Turner syndrome. J Hypertens 2006; 24: 353-60. doi:10.1097/01.hjh.0000200509.17947.0f

9 Sachdev V, Matura L, Sidenko S, et al. Aortic valve disease in Turner syndrome. J Am Coll Cardiol 2008; 51: 1904-9. doi:10.1016/j.jacc.2008.02.035

10 Kim HK, Gottliebson W, Hor K, et al. 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. doi:10.2214/AJR.10.4973

11 Lopez L, Arheart KL, Colan SD. Turner syndrome is an independent risk factor for aortic dilatation in the young. Pediatrics 2008; 121: e1622-27. doi:10.1542/peds.2007-2807

12 Rao PS. Coarctation of the aorta. Curr Cardiol Rep 2005; 7: 425-34. doi:10.1007/s11886-005-0060-0

13 Elsheikh M, Casadei B, Conway GS, et al. Hypertension is a major risk factor for aortic root dilatation in women with Turner's syndrome. Clin Endocrinol 2001; 54: 69-73. doi:10.1046/j.1365-2265.2001.01154.x

14 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. National Heart, Lung, and Blood Institute, Bethesda, Maryland. Pediatrics 2004; 114: 555-76. doi:10.1542/peds.114.2.S2.555

15 Routledge FS, McFetridge-Durdle JA, Dean CR. Night-time blood pressure patterns and target organ damage: A review. Can J Cardiology 2007; 23: 132-8. doi:10.1016/S0828-282X(07)70733-X

16 Lurbe E, Cifkova R, Cruickshank JK, et al. European Society of Hypertension. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens 2009; 27: 1719-42. doi:10.1097/HJH.0b013e32832f4f6b

17 Nathwani NC, Unwin R, Brook CGD, et al. The influence of renal and cardiovascular abnormalities on blood pressure in Turner syndrome. Clin Endocrinol 2000; 52: 371-7. doi:10.1046/j.1365-2265.2000.00961.x

18 Hammerness PG, Perrin JM, Shelley-Abrahamson, et al. Cardiovascular risk of stimulant treatment in pediatric attention-deficit/hyperactivity disorder: update and clinical recommendations. J Am Acad Child Adolesc Psychiatry 2011; 50: 978-90. doi:10.1016/j.jaac.2011.07.018

19 Ankarberg-Lindgren C, Elfving M, Wikland KA, et al. Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls. J Clin Endocrinol Metab 2001; 86: 3039-44.

20 Langrish JP, Mills NL, Bath LE, et al. Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure. Hypertension 2009; 53: 805-11. doi:10.1161/HYPERTENSIONAHA.108.126516

21 Chalard F, Ferey S, Teinturier C, et al. Aortic dilatation in Turner syndrome: the role of MRI in early recognition. Pediatr Radiol 2005; 35: 323-6. doi:10.1007/s00247-004-1359-5

22 Ostberg JE, Donald AE, Halcox JPJ, et al. Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction. J Clin Endocrinol Metab 2005; 90: 516-66. doi:10.1210/jc.2004-0130

23 Gautier M, Detaint D, Fermanian C. Nomograms for aortic root diameters in children using two-dimensional echocardiography. Am J Cardiol 2010; 105: 888-94. doi:10.1016/j.amjcard.2009.11.040

24 Ostberg JE, Brookes JAS, McCarthy C, et al. A comparison of echocardiography and magnetic resonance imaging in cardiovascular screening of adults with Turner syndrome. J Clin Endocrinol Metab 2004; 89: 5966-71. doi:10.1210/jc.2004-1090

25 Lanzarini L, Larizza D, Prete G. Aortic dimensions in Turner's syndrome: two-dimensional echocardiography versus magnetic resonance imaging. J Cardiovasc Med 2007; 8: 428-37. doi:10.2459/01.JCM.0000269716.33435.d3

26 Matura L, Ho VB, Rosing DR, et al. Aortic dilatation and dissection in Turner syndrome. Circulation 2007; 116: 1663-70. doi:10.1161/CIRCULATIONAHA.106.685487

27 Mortensen KH, Hjerrild BE, Stochholm K. Dilatation of the ascending aorta in Turner syndrome-a prospective cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2011; 13: 24. doi:10.1186/1532-429X-13-24

28 Bondy CA. The Turner Syndrome Consensus Study Group. Care of girls and women with Turner Syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007; 92: 10-25. doi:10.1210/jc.2006-1374

29 Bondy CA, Ceniceros i, Van PL, et al. Prolonged rate-corrected QT interval and other electrocardiogram abnormalities in girls with Turner syndrome. Pediatrics 2006; 118: e1220. doi:10.1542/peds.2006-0776

30 Gravholt CH, Juul S, Naeraa RW, et al. Morbidity in Turner syndrome. J Clin Epidemiol 1998; 51: 147-58. doi:10.1016/S0895-4356(97)00237-0

31 Torrance B, McGuire KA, Lewanczuk R. Overweight, physical activity and high blood pressure in children: a review of the literature. Vasc Health Risk Manag 2007; 3: 139-49.

32 SIGN national guideline 115; Management of obesity. February 2010. http://www.sign.ac.uk/guidelines/fulltext/115/index.html (accessed 23 Sep 2014 ).

33 Hata K, Nakagawa T, Mizuno M, et al. Relationship between smoking and a new index of arterial stiffness, the cardio-ankle vascular index, in male workers: a cross-sectional study. Tob Induc Dis 2012; 10: 11. doi:10.1186/1617-9625-10-11

34 Brooke BS, Habashi JP, Judge DP, et al. Angiotensin II blockade and aortic-root dilatation in Marfan's syndrome. N Engl J Med 2008; 358: 2787-95. doi:10.1056/NEJMoa0706585

35 Forte A, Della Corte A, Grossi M, et al. Early cell changes and TGF[beta] pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis. Clin Sci 2013; 124: 97-108. doi:10.1042/CS20120324

36 NICE clinical guideline 127; Clinical management of hypertension in adults. August 2011. http://www.nice.org.uk/guidance/CG127 (accessed 23 Sep 2014 ).