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Aortic and vascular disease
Original research article
Aortic dilatation and outcome in women with Turner syndrome
  1. Anthonie L Duijnhouwer1,
  2. Lidia R Bons2,
  3. Henri J L M Timmers3,
  4. Roland R L van Kimmenade1,
  5. Miranda Snoeren4,
  6. Janneke Timmermans1,
  7. Allard T van den Hoven1,
  8. Marlies Kempers5,
  9. Arie P J van Dijk,
  10. Kathrin Fleischer6,
  11. Jolien W Roos-Hesselink
  1. 1 Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands
  2. 2 Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
  3. 3 Department of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands
  4. 4 Department of Radiology, Radboud University Medical Centre, Nijmegen, The Netherlands
  5. 5 Department of Medical Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
  6. 6 Department of Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands
  1. Correspondence to Dr Anthonie L Duijnhouwer, Department of Cardiology, Radboud University Medical Centre, Nijmegen 6500HB, The Netherlands; toon.duijnhouwer{at}radboudumc.nl

Abstract

Background Women with Turner syndrome (TS) are at increased risk of aortic dissection, which is related to ascending aortic diameter. However, the relation between aortic diameter and outcome is not well determined. This study evaluates the prevalence of aortic dilatation, the growth rate of the aorta and the risk of aortic complications in adults with TS.

Methods Single centre, retrospective study of all women with TS followed with a strict protocol in an outpatient TS clinic. Aortic diameters were analysed using advanced imaging. The primary outcome was a combined endpoint of aortic-related mortality, aortic dissection and preventive aortic surgery. The secondary endpoint was aortic growth and prevalence of aortic dilatation, defined as an aortic size index >20 mm/m2 at baseline.

Results At least one cardiac MR/CT was available in 268 women with TS, having median age of 28.7 (IQR: 21.3–39.7) years. Aortic dilatation was present in 22%. Linear regression identified independent factors associated with larger aortic diameters: age (coefficient=0.23; p<0.001), hypertension (coefficient=2.7; p<0.001), bicuspid aortic valve (coefficient=3.3; p<0.001), 45XO karyotype (coefficient=1.7; p=0.002), weight (coefficient=0.075; p<0.001) and growth hormone treatment (coefficient=1.4; p=0.044). During follow-up (6.8±3.2 years), five women (2%) reached the primary endpoint (two dissections, three aortic surgery). Women withmore than one scan (n=171; 1015 patient-years follow-up), the median aortic growth was 0.20 (IQR: 0.00–0.44) mm/year. In multivariate analysis, aortic growth was not associated with baseline aortic diameter or other variables.

Conclusions Aortic dilatation is common and known associations were confirmed in large adult TS cohort However, aortic dissection, related mortality and preventive aortic surgery are rare. Growth hormone treatment in childhood was associated with aortic dimensions.

  • aortic and arterial disease
  • congenital heart disease
  • aortic aneurysm

https://doi.org/10.1136/heartjnl-2018-313716

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    Introduction

    Turner syndrome (TS) is a rare disorder, caused by partial or total absence of an X-chromosome. Prominent features are short stature, gonadal dysgenesis and congenital heart defects. Most commonly seen cardiovascular abnormalities are bicuspid aortic valve (BAV), partial anomalous pulmonary venous return, elongation of the transverse aortic arch, aortic coarctation and ascending aortic dilatation.1–3 Depending on the definition, the prevalence of aortic dilatation ranges from 4% to 42%.4 5 In patients with TS, aortic dissection is reported to occur six times more often compared with the general population.1 Reported associated factors of aortic dissection are the presence of BAV, aortic coarctation, dilatation of the aorta, hypertension and pregnancy. Dilatation of the aorta occurs predominantly at the level of the ascending aorta and is associated with dissection.6 7 European Society of Cardiology guidelines advise to correct for body surface area (BSA) in small body size patients.8 For the ascending aortic diameter, this index is called the aortic size index (ASI). Preventive aortic surgery is advised when the ASI exceeds 27.5 mm/m2, but this cut-off value is mainly derived from extrapolation of thoracic aortic dissection in women with non-TS with mostly normal height and higher age.8 Other guidelines advise preventive surgery even with lower ASI (>25 mm/m2), mainly based on registries of aortic dissection.9 The relation between aortic diameters and clinical outcome in patients with TS is not studied in large prospective studies. Increase in aortic diameters over time is theoretically expected to be more rapid in patients with a dilated aorta based on Laplace’s law and is also expected to be associated with the same factor that also are associated with aortic dilatation, but whether this is true for patients with TS is also not well investigated.10

    In this cohort study of women with TS, we describe the prevalence of ascending aorta dilatation, growth of the aorta over time and sought to identify factors associated with clinical outcome.

    Methods

    Population

    In March 2003, a dedicated multidisciplinary adult TS outpatient clinic was established at Radboud University Medical Centre and a standard protocol for assessment and follow-up was initiated.11 The diagnosis of TS was made based on karyotyping of at least 30 blood lymphocytes. All TS karyotypes were included and divided in two main groups 45X0 and mosaicism (non-45X0), in which the mosaicism group is divided in six groups (online supplementary 1). A strict follow-up protocol was followed.8 As part of their multidisciplinary evaluation, patients were routinely investigated by a cardiologist with ECG, echocardiography and cardiac MRI (CMR) or when contraindicated CT and by an endocrinologist and gynaecologist. The yield of this standardised health screening in the initial 100 patients of our cohort was published previously.11 All women with TS visiting this specialised outpatient clinic were eligible for inclusion. For this retrospective study, we included all women with TS who had at least one CMR/CT at adult age and the images had to be available for review. For the study on aortic growth, all patients with at least two CMR/CT were included. BSA was calculated using the Dubois formula.12 Ascending aortic dilatation was defined as an ASI≥20 mm/m2. Z-scores for every patient were calculated based on the formula published by Campens et al.13 Hypertension and hypercholesterolaemia were defined following guidelines and ‘requiring medical therapy’. The Institutional Ethical Board (CMO Arnhem-Nijmegen) approved this study and concluded that no informed consent was needed as the treating doctors performed the study and the institution adopted an opt-out policy on scientific medical file research. All data were handled carefully and confidentially.

    Supplemental material

    Advanced imaging

    Baseline and follow-up aortic diameters were measured by a dedicated radiologist using CMR or when contraindicated CT. In all CMR/CT a standard imaging protocol was used. An Avanto 1.5 T whole-body MRI system was used (Siemens). Dedicated phased-array cardiac surface coils were placed over the thorax. All images were acquired with breath-hold. The ascending aorta was measured on axial TRUFI images in the axial plane.

    For CT acquisition, a 320 slice scanner (Aquilion one, Toshiba) was used. The heart was fully covered within a wide volume scan with ECG gating during the whole heart cycle. The ascending aorta was measured in the axial plane, during diastolic phase. In both modalities, an inner edge to inner edge method was used to measure the ascending aortic diameter at the height of the right pulmonary branch.11 Both the absolute measurements and measurements corrected for BSA (ASI) were collected.

    Endpoints

    The primary endpoint was an aortic event, defined as aortic-related mortality (proven or high suspicion of dissection or rupture), aortic dissection or (preventive) aortic surgery. Information on the vital status of all participants was obtained from the municipal base administration of personal data (GBA) of the Netherlands on 1 February 2017.

    The secondary endpoint was the increase in ascending aortic diameters which was assessed in the patients with more than one CMR/CT. Patients who reached the primary endpoint before having the second CMR/CT were excluded from this analysis. The annual change of the aortic diameter was calculated based on the aortic diameter measurements of the first and last scan, divided by the time span between these scans. Because of this, negative aortic diameter change could occur.14

    Statistical analysis

    Results are expressed as mean±SD or as median±IQR if the distribution was skewed or the Shapiro-Wilk test showed abnormal distribution. A p≤0.05 was defined to be statistically significant. The independent samples t-test was used to compare means (eg, aortic growth/year) between groups. In case of a skewed distribution, the Mann-Whitney test was used. The paired sample t-test was used to compare ascending aortic diameter change in time within cases. Univariate and multivariate linear regression analyses were used to explore associations with aortic diameter and aortic growth, or logistic regression analysis was used to explore associations with aortic dilatation and aortic growth using the same variables. Survival analysis could not be performed due to the limited number of events.

    Results

    In total, 270 patients with TS were eligible, of whom 2 had to be excluded due to poor-quality aorta images. The remaining 268 patients, median age of 28.7 (IQR: 21.3–39.7) years and mean height of 155.2±7.2 cm, had at least one CMR/CT with adequate imaging and were included in the current study. During follow-up, 171 patients with TS had at least one other CMR/CT (figure 1). For the other patients, additional CMR/CT imaging was not available due to various reasons (eg, care transfer, refusal by patient, lost to follow-up, short period since first scan). No differences were found in baseline characteristics between the patients with versus without more than one scan.

    Figure 1
    Figure 1

    Flow diagram of patient inclusion. *Due to artefacts, the CMRs were not suitable for measuring the diameter of the ascending aorta. ASI, aortic size index; CMR, cardiac MRI.

    Baseline

    Characteristics of all 268 included patients at baseline are shown in table 1. Dilatation of the ascending aorta (ASI>20 mm/m2) was present in 59 (22%) patients. Mean z-score was 0.91±1.50 and 22.8% had an z-score ≥2. The mean age of the patients with TS and a dilatated ascending aorta was significantly higher compared with patients with TS without dilatation 40.9 (IQR: 29.0–47.3) versus 25.9 (IQR: 20.5–34.8) years, p<0.001. The prevalence of hypertension was significantly higher in the women with dilatation (33.9% vs 12.1%; p<0.001). Figure 2 shows the uncorrected and corrected ascending aortic diameters at baseline for all patients according to age. At the age of 35 years, the upper 95% line crosses the ASI=25 mm/m2 line. In total, 13 patients had an ASI>25 mm/m2, mean age of 44.3±7.7 years versus 30.4±10.8 years in ASI<25 mm/m2. Baseline uncorrected ascending aortic diameter was independently associated with age, hypertension, BAV, 45X0 karyotype, weight and growth hormone treatment (table 2). Although the p-value for aortic coarctation in univariate analysis was <0.10, we excluded it from the model. The reason for this were: the SE was larger than the coefficient, the number of women with aortic coarctation was low and multivariate analysis using backward selection with p<0.1 excluded coarctation out of the model.

    View this table:
    Table 1

    Characteristic of patients with TS with or without aortic dilatation at baseline

    Figure 2
    Figure 2

    Ascending aortic diameter at baseline corrected and uncorrected versus age. (A) Aortic size index versus age; (B) ascending aorta diameter corrected for height versus age; (C) absolute ascending aortic diameter versus age; (D) z-score at baseline versus age. Cases 41, 42 and 231 underwent aortic preventive surgery. Case 231 had aortic valve dysfunction as primary indication. Case 129 is a patient who had presumably a type A dissection. Case 219 had a body mass index of 40.5 kg/m2 and an ascending aorta of 41 mm. Case 213 is a patient who has an ascending aortic diameter of 39 mm and a body surface area of 1.33 kg/m2. The centre line represents the mean of y-axis variable and the upper and lower line represent the 95% limit of the mean of y-axis variable.

    View this table:
    Table 2

    Univariate and multivariate linear regression analysis for the association of absolute ascending aortic diameter at baseline

    The significant adjusted odds ratios for ASI>20 mm/m2 are presented in figure 3.

    Figure 3
    Figure 3

    Forest plot of adjusted odds ratios for aortic dilatation at baseline in women with Turner syndrome. R2=38.1%. Aortic dilatation was defined as an aortic diameter >20 mm/m2 body surface area.

    A history of growth hormone treatment during childhood was reported in 161 (60%) patients. Compared with patients who were treated with growth hormone, the non-treated group was significantly older (mean age 39.3±10.7 vs 25.0±6.8 years; p<0.001). As a consequence of the relative recent introduction of synthetic growth hormone treatment, younger age patients were more likely to have been treated with growth hormone. The mean aortic diameter and ASI unadjusted for age were smaller for patients who were treated compared with the non-treated group (27.2±4.8 vs 29.1±5.2 mm; p=0.004 and 16.9±3.1 vs 18.9±4.1 mm/m2; p<0.001). However, after correcting for variables shown in table 2, previous growth hormone treatment was still associated with a larger ascending aortic diameter.

    Follow-up

    Survival status was available for all patients. In total, eight patients died during a mean follow-up of 6.8±3.2 years. These eight cases are described in table 3. In two patients, the cause of death was assumed to be related to aortic dissection (case 129; case 4). Case 129 was a 44-year-old patient with TS with an ascending aortic diameter of 65 mm (ASI=39.2 mm/m2), who delayed her operation to get married and died suddenly. No autopsy was performed. Case 4 was also 44 years old and died from acute dissection of the descending aorta. This patient had normal ascending (30 mm; ASI=18.4 mm/m2) and descending (25 mm) aortic diameters on CMR 3.5 years prior to this event. Preventive ascending aortic surgery was performed in three patients. In two patients, the indication for surgery was ascending aortic dilatation (45 mm; 48 mm or ASI=28 mm/m2; ASI=25.5 mm/m2, respectively) and in one patient the indication was severe aortic valve regurgitation with concomitant moderate ascending aortic dilatation (36 mm; ASI=22.9 mm/m2). The primary endpoint was therefore reached in five patients. Because of the limited number of events, no analysis on predictors could be performed.

    View this table:
    Table 3

    Causes of death in women with TS

    Aortic growth

    In total, 171 (64%) patients had more than one CMR/CT during follow-up (figure 1). There was a significant increase in ascending aortic diameter per patient (1.2±2.3 mm; p<0.001) in a mean follow-up time of 5.9 (range: 1.1–11.3) years and a total of 1015 patient-years. Ascending aortic diameter increase per year was 0.20 (IQR: 0.00–0.44) mm/year.

    The median ascending aortic diameter change in the whole cohort was 0.43 (IQR: 0.00–0.43) mm/year. The mean time between the first and last CMR/CT was not significant different between the women with TS who had a dilated and non-dilated ascending aorta (6.2±2.4 vs 5.9±2.1; p=0.51). The median ascending aortic diameter change in the dilated group was 0.00 (IQR: −0.20 to 0.31) mm/year and 0.24 (IQR: 0.00–0.44) mm/year in the non-dilated group (p=0.021). No significant difference was found in ascending aortic diameter change between patients with (n=38) or without BAV (n=133) 0.16 (IQR: −0.02 to 0.37) mm/year versus 0.22 (IQR: 0.00–0.44) mm/year, p=0.75). There was a difference in patients with (n=29) or without (n=142) hypertension 0.00 (IQR:−0.22 to 0.30) mm/year versus 0.23 (IQR: 0.00–0.44) mm/year, p=0.04). Eight women showed an increase in ascending aorta diameter of ≥1 mm/year. Of the nine women who had an ASI>25 mm/m2 at baseline, one underwent preventive aortic surgery and one experienced an aortic complication during follow-up.

    During the study period, four women became pregnant, and median change in aortic diameter was 0.05 (IQR: −0.17 to 0.97) mm/year versus 0.20 (IQR: 0.0– 0.43) mm/year for the other women (p=0.84).

    Figure 4 shows the change in ascending aortic diameter for all 171 patients, related to baseline ascending aortic diameter (both uncorrected and corrected for BSA). The three operated cases had a growth varying between 0.33 and 1.22 mm/year and the woman with presumed type A dissection had an ascending aortic growth of 3.25 mm/year (not presented in figure 4). Univariate linear regression identified two associations with aortic growth, hypertension, and aortic dilatation at baseline, which were not significant in multivariate analysis. Based on the upper quartile of ascending aortic change (0.43 mm/year), the TS cohort was divided in two groups. Logistic regression did not identify significant associations for aortic growth ≥0.43 mm/year. Figure 5 shows the unadjusted HRs in a forest plot of all tested variables.

    Figure 4
    Figure 4

    Corrected and uncorrected ascending aortic diameter change versus baseline corrected and uncorrected ascending aortic diameter. (A) Ascending aortic change versus aortic size index at baseline; (B) ascending aortic change versus ascending aorta diameter corrected for height at baseline; (C) ascending aortic change versus absolute aortic diameter at baseline; (D) ascending aortic change versus z-score at baseline. Case 129 (diameter change of 3.25 mm/m2) is not presented in these figures.

    Figure 5
    Figure 5

    Forest plot of unadjusted HRs for aortic growth. Aortic growth was defined as aortic diameter increase >0.42 mm/year. ACE-I, ACE inhibitors; ARB, angiotensin II receptor blockers; ASI, aortic size index; FU, follow-up; previous GHT, previous growth hormone treatment during childhood.

    Discussion

    This study describes one of the largest TS cohorts to date, in which aortic dimensions are measured using advanced imaging during a relative long follow-up time. Aortic dilatation was present in one-fifth of women with TS at a mean age of 29 years. Classical factors associated with larger aortic diameters were age, hypertension, BAV, 45X0 karyotype, weight, and growth hormone treatment. During almost 7 years of follow-up, only 2% of the women suffered an aortic event and no unexpected ascending aortic complications occurred. The aortic growth rate was low (0.20 mm/year), but higher than reported in the normal population (0.12 mm/year).13 14 Classical factors associated with larger aortic diameters, such as a BAV, were not associated with faster growth of the ascending aortic diameter. Also, an initial larger aortic diameter was not associated with faster growth.

    Ascending aortic dilatation

    As shown by others, current study shows that also in women with TS age has a clear impact on aortic diameter.15 This association with age is also observed in the general population.13 16 This relation is not linear but rather more curved and levelling-off at older age. In the current TS guidelines, no correction is made for age, which seems indicated. At a median age of 29 years, 22% of the women with TS have a dilated aorta (ASI>20 mm/m2). Maybe this high prevalence is partly caused by the ASI method. One of the pitfalls of the ASI method is that the ASI becomes lower in obese patients (case 219) and relative larger in slim patients (case 213). Due to this ‘overcorrection’ of the aortic diameter, some women with TS will be labelled as having a normal aortic diameter. Correcting the aortic diameter using height instead of BSA could partly solve this problem. This is especially important when realising that ASI is the main indicator for preventive surgery. Recent publications have shown that z-scores used for people with a normal height are also fit for women with TS.13 15 The z-score was ≥2 in 22.8% of the women in this cohort. This is comparable with the ASI method. Indeed, both the z-score method and the ASI method correct for weight and height. It seems more appropriate to use ASI or z-score in women with TS with a normal BMI and be cautious in women with a very low or very high BMI.

    The cross-sectional analysis confirmed the known factors associated with aortic dilatation.4 In addition to these known associations, our data suggest that growth hormone treatment during childhood is associated with larger aortic diameter even after correcting for age and height. Due to multicollinearity with age and the chance of having being treated with growth hormone, this effect should be interpreted with caution. Dedicated research is warranted to investigate the long-term effect of growth hormone treatment on aortic diameters, aortic wall composition and vulnerability.

    Olivieri et al found that a partial cusp fusion was associated with larger aortic diameters.17 In the current study, we did not use this partial cusp fusion.

    Aortic growth

    Even though older patients with TS generally have a larger ascending aorta, we do not know if these larger dimensions also lead to higher risks of aortic complications. It seems logical that dilatation occurring at younger age is associated with more aggressive aortic pathology. In the literature, the mean age at which patients with TS present with aortic dissection is 32 years.4 18–20 The age of both patients with dissection in our series was 44 years, so also still relatively young. Others showed that especially younger adult women with TS who had a dilatated aorta are vulnerable and that after a certain age the risk of aortic dissection decreases.7

    Limited publication on aortic growth in women with TS are available. A prospective study would be the best study design. Our study is retrospective, but because of the standardised follow-up, the use of CMR/CT scans and the inclusion of all patients referred to our hospital without selection bias, we believe this to be the second-best option to study aortic growth. The observed increase in aortic diameters in the current study is low, but higher than reported in the general population.13 Univariate analysis suggested that hypertension and baseline aortic dilatation were associated with aortic growth, but in multivariate analysis they were no longer significant. Possibly that treatment of hypertension protected these women against accelerated aortic growth. The low increase in aortic diameter and the relative short follow-up time could be an explanation for not finding any independent associations for aortic diameter change.

    Mortensen et al developed an aortic diameter prediction model using complex mathematical processing based on the follow-up of 78 women with TS over a period of almost 5 years. These cohesive models identified predictors of accelerated aortic growth (aortic coarctation, BAV, age, diastolic blood pressure, BSA and antihypertensive treatment).7 In our study, we could not confirm these findings. Heterogeneity of karyotypes present in patients with TS has been shown. In most cases, blood lymphocytes are used for the diagnosis and sometimes additional buccal cells are used. Different cell lines can show different karyotypes, making it possible that the karyotype of the aortic wall differ from the cell line used for diagnosis.21 The aortic wall properties may therefore be not well presented by the used karyotypes.

    Outcome

    In 7 years of follow-up, the incidence of aortic complications was 2%. This low incidence of 0.3 %/year immediately illustrates the difficulty of identifying risk factors of aortic complications in women with TS. On the other hand, it is important information that the absolute risk is very low, although still higher than in women with non-TS.1 Our data certainly do not support a more aggressive approach towards surgery. The indication for surgery is still matter of debate. Pape et al showed, in a large cohort of patients, that in 50% of the patients with a dissection, the aortic diameter was below the advised surgical aortic diameter threshold.22 This clearly shows that, aortic diameter as sole parameter on which preventive aortic surgery is advised in current guidelines is not sufficient enough to prevent future aortic dissections.8 9 23 24 Future research should focus on other parameters to better predict future aortic dissection risk.

    Limitations

    Although we have included all patients, selection bias due to referral cannot be excluded. However, if selection bias has taken place, the more severe cases would have been sent to our tertiary clinic and therefore the relatively positive and reassuring results would only have been more positive. Indeed, information on survival and events was 100% complete. The used z-score is based on echocardiographic measurements and could differ from a z-score based on CMR/CT measurements.

    Key messages

    What is already known on this subject?

    • Aortic dilatation is common in women with Turner syndrome (TS) and is associated with the risk of aortic dissection.

    • Currently, the main indication for preventive aortic surgery in women with TS is based on aortic size index, regardless of age and body composition.

    What might this study add?

    • This study reports associations between age and aortic diameter and previous growth hormone treatment with larger aortic diameters. In a large TS cohort, the outcome was good and the aortic growth rate, assessed with advanced imaging, was slow but faster compared with the general population, in a mean follow-up time of almost 7 years. The incidence of events was low.

    How might this impact on clinical practice?

    • Age and weight are important determinants of aortic size index and should be taken into account whenever a decision is made about whether or not a preventive aortic surgery is advised.

    • Next to aortic size index, age and weight should therefore be incorporated in future guidelines on preventive aortic surgery in women with TS.

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    Footnotes

    • Contributors ALD conducted the study and wrote the manuscript. ALD, JWR-H constructed the main outline of this study. MK, ALD collected the data. LRB, ALD, ATvdH contributed in statistical analysis. MS, APJvD, LRB performed the CMR measurements. HJLMT, RRLvK, JT, ATvdH, MK, APJvD, KF, JWR-H helped in writing the final version of the manuscript.

    • Funding This study was funded by a grant of the Dutch Heart foundation (grant no: 2013T093).

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval The Institutional Ethical Board (CMO Arnhem-Nijmegen) approved this study (ID 2016-3004).

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