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Department of Endocrinology (J.E.O., C.M., G.S.C.), University College London Hospitals, London W1T 3AA, United Kingdom; and Vascular Physiology Unit (A.E.D., J.P.J.H., C.S.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom
Address all correspondence and requests for reprints to: Dr. Gerard Conway, Department of Endocrinology, The Middlesex Hospital, Mortimer Street, London W1T 3AA, United Kingdom. E-mail: g.conway{at}ucl.ac.uk.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: We hypothesized that TS women have a fundamental arterial wall defect that may be due to genetic factors or estrogen deficiency.
Design, Setting, and Patients: TS women (n = 93) were compared with normal controls (n = 25) and women with 46,XX primary amenorrhea (PA) (n = 11) with a similar history of estrogen deficiency. Clinical parameters, aortic root diameter, extraaortic arterial structure [common carotid (CD), brachial artery diameter, and carotid intima-media thickness (IMT)], arterial stiffness (pulse-wave velocity, augmentation index), and endothelial function (flow-mediated dilatation) were assessed.
Main Outcome Measures: These included arterial diameters and vascular physiology parameters.
Results: Differences in arterial structure were observed among TS, normal controls, and 46,XX PA women: IMT (0.61 ± 0.07 vs. 0.55 ± 0.06 vs. 0.60 ± 0.05 mm, respectively; P < 0.001), CD (5.71 ± 0.64 vs. 5.27 ± 0.34 vs. 5.22 ± 0.38 mm; P < 0.001), and brachial artery diameter (3.29 ± 0.44 vs. 3.06 ± 0.36 vs. 2.97 ± 0.30 mm; P = 0.006). Aortic root diameter was greater in TS than normal control women. TS status, height, weight, and IMT were independently associated with increased CD after multivariate adjustment (P < 0.05). TS status, age, diastolic blood pressure, and CD remained independently associated with increased IMT after multivariate adjustment (P < 0.05). Pulse-wave velocity and flow-mediated dilatation were similar among the three groups.
Conclusion: Women with TS have greater IMT and conduit artery diameters than normal controls. Similarly, increased IMT in TS and 46,XX PA women suggests that estrogen deficiency contributes to intimal thickening. Interventional studies are required to determine the extent to which blood pressure and estrogen deficiency may be appropriate therapeutic targets to reduce cardiovascular risk in TS.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although the aortic abnormalities of TS such as aortic root dilatation and coarctation, are well recognized (14, 15), we hypothesized that women with TS have a fundamental arterial wall defect extending beyond the arch of the aorta. This may be related to genetic factors or estrogen deficiency. The present study set out to characterize the vasculopathy of TS by assessing arterial structure [carotid (CD) and brachial artery diameter (BD) and carotid artery intima media thickness (IMT)], arterial stiffness [pulse-wave velocity (PWV) and augmentation index (AIx)] and endothelial function [brachial artery flow-mediated dilatation (FMD)].
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Clinical history and case notes were reviewed for previous medical history and cardiac surgery. History of estrogen replacement and previous GH administration, smoking, and exercise were recorded, and current medications, especially the use of antihypertensives, were noted. All women with TS and normal controls underwent echocardiography.
Subjects attended after a 12-h overnight fast, and a blood sample was taken before vascular physiology assessment for analysis of lipids, glucose, insulin, and karyotype. The homeostasis model insulin resistance index was calculated as the product of fasting insulin and glucose concentrations divided by 22.5. Antihypertensive medication was withheld for at least 24 h. Anthropometric parameters were assessed including height, weight, and waist and hip measurements. Recumbent blood pressure was recorded at the right brachial artery using an automated sphygmomanometer (Dinamap, Critikon, Tampa, FL) after subjects had rested for at least 15 min. Five readings were taken and mean systolic and diastolic blood pressure calculated. A large cuff was used for obese individuals.
PWV and AIx
PWV was determined with the subject supine, using a transcutaneous pressure tonometer (SphygmoCor system, AtCor Medical, West Ryde, NSW, Australia) to record the pulse pressure waveform consecutively at the carotid and femoral artery. The distance traveled by the pulse wave was measured over the body surface, and the pulse wave velocity (in meters/second) was derived from the mean time difference between the R-wave measured in a simultaneously recorded electrocardiogram and pressure wave in relation to the arterial path length.
AIx was calculated using the radial pulse pressure waveform to derive the central pressure waveform using a validated generalized transfer function. This was then corrected for heart rate.
CD and IMT measurement
CD was measured 1 cm below the common carotid artery bifurcation using high resolution B-mode real-time ultrasound (Acuson XP10 ultrasound system) with a 5–10 MHz linear array transducer. Ultrasound images were recorded on videotape and interpretation of scans was performed by a single blinded analyzer. CD was calculated from the end-diastolic distance between the lumen-intima interfaces measured in three sequential R-wave-triggered frames, whereas IMT was defined by the lumen-intima and media-adventitia interfaces of the far wall. Three measurements were taken for both parameters on each side, and the mean of right and left taken as the overall average CD and IMT respectively.
BD and flow-mediated dilatation (FMD) measurement
High-resolution ultrasound was used to determine the change in BD in response to the hyperemic stimulus mediated by 5 min of forearm ischemia and also in response to 25 µg glyceryl trinitrate (GTN) as previously described (16). Off-line analysis was performed using an edge-detection software package (Brachial Tools, Medical Imaging Applications, Iowa City, IA).
All vascular physiology measurements were undertaken by two experienced vascular technologists. Blinded replicate measures were performed to assess reliability and found inter- and intraobserver correlation coefficients to be 0.96 and 0.99, respectively. Masked analysis of videotape-recorded scans and computing of results was performed by a single analyzer.
Echocardiography
M-mode and two-dimensional echocardiography was undertaken in the women with TS and the normal controls (Aspen echocardiography machine; Acuson, Mountain View, CA). Measurements of aortic root diameter (ARD) at the level of the annulus and the presence of BAV were recorded.
Statistical analysis
Published data in the general population have shown that an increase in IMT in the common carotid artery correlates with an 11% increase in risk of myocardial infarction (17). Using pilot data in 18 subjects with TS, compared with controls, we calculated that for a power of 90% and a significance level of 0.05, 22 subjects would be required in each group to detect a mean ± SD difference in IMT of 0.4 ± 0.4 mm. Because TS is a heterogeneous condition, we opted to recruit 93 subjects to allow for analysis of effects in subgroups, such as those who had received GH (30%) or those with monosomy X as opposed to other karyotypes (48%). Eleven women with 46,XX PA were recruited for illustration of the effect of estrogen deficiency.
Statistical analysis was performed using SPSS (version 11.0 for Windows, SPSS, Inc., Chicago, IL). Associations among variables were assessed using Pearson’s correlation coefficient and ANOVA or Student’s t test for continuous variables, with log transformation and Scheffé post hoc analysis where appropriate and controlling for cofactors when indicated. Spearman’s correlation coefficient was used for nonparametric and categorical variables. Estrogen exposure in TS and 46,XX PA groups was compared by Mann-Whitney U test. Linear regression analysis (entry method) was used to assess strength and independence of associations between variables.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Women with TS were shorter and had greater body mass index (BMI), waist circumference, systolic and diastolic blood pressures, and heart rate than women in the normal control and 46,XX PA groups (Table 1
). They smoked less (85 vs. 60 vs. 36% had never smoked in TS, normals, and 46,XX PA groups, respectively; P < 0.001) and took less exercise (15 vs. 48 vs. 36% took regular moderate or vigorous exercise in the three groups, respectively; P < 0.001). Four women with TS had type 2 diabetes mellitus.
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2 test; P = 0.127). Also, 30.1% of TS women had previously been treated with GH, with a median (range) start age of 10 [5–17) and 4.5 (0.5–10)] yr duration of treatment. In addition, 48.4% of the women with TS had karyotype 45,X. Other karyotypes in the TS group included isochromosome X (29%), partial X deletion (2.2%), ring X (8.6%), any Y fragment (4.3%), mosaic 45X/46XX (4.3%), and complex forms (3.2%).
A BAV was identified in 17 (18%) women with TS, and six women were known to have significant aortic coarctation from our previous magnetic resonance imaging study (14). Two women with TS had aortic stenosis (peak aortic valve gradients 31 and 42 mm Hg, respectively), of whom one also had BAV, and these subjects were excluded from the analyses of AIx. Twenty women were taking antihypertensive medication (nine on atenolol, five on an angiotensin-converting enzyme inhibitor, four on bendrofluazide, one on an angiotensin II receptor antagonist, and one on a calcium channel antagonist). Both exclusion of the women with each category of complications individually and all TS women with any complication (n = 32) did not alter the relationship between TS status and the vascular parameters studied except augmentation index as mentioned above. The data presented for TS throughout the study are therefore inclusive of all TS women unless otherwise stated, although Table 2 demonstrates the main outcome measures in TS women with and without complications for reference.
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Comparison of arterial structure.
Women with TS had greater absolute and height-adjusted CD than women in the normal control and 46,XX PA groups (Table 3). This relationship remained after adjusting for factors that were associated with CD in women with TS (see below): height, weight, and IMT (P < 0.001). Group differences were also significant for absolute and height-adjusted BD. Relative differences in arterial diameters between women with TS, compared with controls, are shown in Fig. 1.
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). These group differences remained significant after adjustment for factors that were associated with IMT in women with TS (see below): age, diastolic blood pressure, and CD (P = 0.002).
Comparison of arterial stiffness.
PWV was similar in all three groups of women. AIx was greater in women with TS than the other two groups, but the difference among these groups was no longer significant after adjustment for height (Table 3).
Comparison of brachial artery vasomotor function.
FMD was similar in the three groups, with and without adjustment for the magnitude of the flow stimulus (Table 4). Vasodilator responses to GTN were also similar.
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Factors associated with arterial structure. CD was associated with height (r = 0.340; P = 0.001), weight (r = 0.383; P < 0.001), total cholesterol (r = 0.228; P = 0.030), carotid IMT (r = 0.254; P = 0.015), and FMD (r = –0.233; P = 0.026). The associations between CD and both BD and ARD (mean ± SD 2.8 ± 0.4 cm) did not achieve significance (r = 0.208; P = 0.054 and r = 0.199; P = 0.059, respectively). On multiple regression analysis, height (partial r = 0.245; P = 0.019), weight (partial r = 0.247; P = 0.019), and carotid IMT (partial r = 0.277; P = 0.004) were found to be independently associated with CD. Similar associations were observed with BD.
ARD was greater in the 17 women with BAV, compared with those without (3.0 ± 0.4 vs. 2.8 ± 0.4 cm; P = 0.040), but CD and BD were not influenced by BAV (CD 5.6 ± 0.6 vs. 5.7 ± 0.6 cm; P = 0.416; BD 3.3 ± 0.3 vs. 3.3 ± 0.5 cm; P = 0.882 in women with and without BAV, respectively).
Carotid IMT was associated with age (r = 0.488; P < 0.001), systolic blood pressure (r = 0.325; P = 0.002), diastolic blood pressure (r = 0.370; P < 0.001), CD (r = 0.277; P = 0.004), and AIx (r = 0.441; P < 0.001). On multiple regression analysis, age (partial r = 0.358; P < 0.001), diastolic blood pressure (partial r = 0.222; P = 0.043), and CD (partial r = 0.220; P = 0.012) were independently associated with IMT. History of smoking, exercise, diabetes mellitus, previous GH treatment, karyotype, and the presence of a BAV, aortic stenosis, and coarctation site abnormalities were not associated with CD or IMT.
Factors associated with arterial stiffness.
PWV and AIx increased significantly with age (PWV, r = 0.326; P = 0.002; Aix, r = 0.397; P < 0.001) and both systolic and diastolic blood pressure (P 
0.001). Neither PWV nor AIx was associated with weight, lipids, smoking history, exercise, or karyotype. Variation in the use of GH in childhood and cumulative years of estrogen deficiency were not associated with PWV or AIx after adjustment for age. PWV and AIx were similar in those with and without BAV.
Determinants of endothelial function. FMD was independently associated with waist circumference (partial correlation coefficient, r = –0.206; P = 0.039), total cholesterol concentration (r = –0.215; P = 0.032), and heart rate (r = 0.303; P = 0.002).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The occurrence of aortic dilatation in TS is well established (4, 18, 19). It has been associated with the presence of BAV, aortic coarctation, and hypertension, but its etiology is poorly understood. We observed that although ARD was greater in women with TS who have BAV, arterial dilatation is not restricted to these individuals and also occurs in other large conduit vessels, such as the carotid and brachial arteries, to a similar extent in those with and without BAV.
We have demonstrated that CD is independently associated with TS status, height, weight, and carotid IMT. However, in contrast to women with TS and despite a greater degree of estrogen deficiency, karyotypically normal women with primary amenorrhea had normal CD and BD, thus suggesting that genetic factors rather than estrogen deficiency have a greater influence on arterial dilatation in TS. The absence of an independent association between peripheral arterial diameter and BAV, aortic stenosis, or blood pressure suggests an intrinsic abnormality of the arterial wall in TS. An analogy to the arterial dilatation seen in Marfan syndrome has been postulated (18, 20). Indeed, cystic medial necrosis similar to that in Marfan syndrome has been reported in 65% of TS case reports of aortic dissection, in which histology was available (3, 21, 22).
The apparent relationship between generalized arterial dilatation and increased IMT may, in part, be consistent with the Glagov phenomenon (23). This refers to the outward remodeling and enlargement of atherosclerotic arteries as a consequence of complex inflammatory changes in the vascular wall that compensates for luminal occlusion in the earlier stages of disease development. For example, increased CD was independently associated with IMT as well as the presence of atherosclerotic plaques and increased blood pressure in a population-based study of older subjects (24). Increased IMT is a marker of early carotid atherosclerosis and an independent predictor of an adverse cardiovascular prognosis in the general population (17). In our study, IMT was greater in TS than control women but similar between TS and 46,XX PA groups. However, the fact that CD was increased only in the TS group suggests that factors other than the Glagov phenomenon are involved. In the general population, IMT has been shown to be associated with traditional risk factors for ischemic heart disease, such as age, blood pressure, serum lipids, smoking, diabetes mellitus, and BMI (17, 25). In this study of younger women, the major influences on variation of IMT measurements were TS, normal, or 46,XX PA status; age; and blood pressure. Although women with TS had raised blood pressure, compared with the other two groups, this did not appear to account for their greater IMT as the difference persisted when only uncomplicated cases were considered (Table 2). Indeed, the similar increase in IMT seen in TS and 46,XX PA women implicates estrogen deficiency as the key determinant of neointimal hyperplasia in these subjects.
Estrogen deficiency may, therefore, be an appropriate target for early intervention in both TS and 46,XX PA to reduce progression of intimal thickening, and ultimately clinical atherosclerotic disease, although interventional studies will be required to prove this point. There is a precedence in the literature, with exogenous estrogen reducing IMT in older postmenopausal women (26, 27, 28), but this is not a universal finding (20, 29). It has been suggested that the reason for this discrepancy is a lack of benefit in women with established coronary artery disease or insufficient duration of estrogen therapy (30).
Our comparisons of measures of aortic stiffness in TS, normal controls, and women with 46,XX PA should be interpreted with caution. Although there was a trend toward greater arterial stiffness, as measured by PWV, this did not achieve statistical significance. It has previously been suggested that PWV may be underestimated in the general population when the abdominal aorta becomes more tortuous with age (31), which may be an important factor in women with TS who frequently have greater tortuosity of the descending aorta (32) and elongation of the transverse arch (15). AIx was greater in women with TS than the other two groups, suggestive of an increased contribution of wave reflection to central aortic systolic blood pressure and left ventricular afterload. However, AIx is influenced by both heart rate and body height and should therefore be corrected for both (33). Although the difference in AIx between TS and controls was lost by height adjustment, there may, however, still be relevance for central aortic pathophysiology and increased cardiac loading because neither the transfer function used nor height adjustment with regard to this measure have yet been validated specifically in women with TS.
PWV is an independent marker of cardiovascular risk (34) and is associated with other cardiovascular risk factors such as blood pressure, insulin resistance, central obesity, and greater carotid IMT in the general population (35). Data on the prognostic value of AIx are still emerging, and some studies suggest that it may have even greater predictive power than PWV (36). Invasive studies would be required for accurate clinical validation of these measures in TS.
It has been shown that endothelium-dependent vasodilator function reflects underlying cardiovascular risk factor burden (37) and independently predicts cardiovascular prognosis (38). We found, however, that FMD was similar in women with TS, compared with normal or 46,XXPA controls, suggesting that endothelial dysfunction is not an important mediator of arterial disease in TS.
Thus far there have been very few studies of arterial dynamics in TS. Two studies have explored the effects of exogenous estrogen in women with TS. Both AIx (39) and the vasodilator response to bradykinin in a plethysmography study (40) have been shown to improve when estrogen-deficient women with TS are treated with estrogen. Our results are similar to those in a recent smaller study that focused on both children and women with TS (41). In general, our findings extend those of Baguet et al. (41) by virtue of the increased power and homogeneous adult estrogen-replete population in the present study. For instance, IMT and CD in TS, compared with controls, achieved significance only when corrected for height in the previous study, an adjustment absolutely required in a pediatric population. In the current study, we demonstrate differences in IMT and CD without height correction. In addition, we extend the observation of dilated arteries to include the brachial and have also studied women with 46,XX PA to control for the estrogen deficiency of TS.
In conclusion, women with TS have arterial dilatation involving not only the aorta but also other major conduit arteries, which does not appear to be a consequence of estrogen deficiency. IMT is also greater in TS than normal controls and appears to be related to the degree of arterial dilatation. This raises the possibility of a common pathway for these two processes, although estrogen deficiency does appear to contribute to intimal thickening in TS. FMD was similar in all groups, excluding an important contribution from conduit arterial endothelial dysfunction. Our findings suggest that both genetic factors and estrogen deficiency influence the vasculopathy of TS. Our data suggest that blood pressure and estrogen deficiency may be the most appropriate modifiable therapeutic targets for cardiovascular risk reduction in TS, but interventional studies will now be required.
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Acknowledgments |
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Footnotes |
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First Published Online June 28, 2005
Abbreviations: AIx, Augmentation index; ARD, aortic root diameter; BAV, bicuspid aortic valve; BD, brachial artery diameter; BMI, body mass index; CD, carotid artery diameter; FMD, flow-mediated dilatation; GTN, glyceryl trinitrate; IMT, intima-media thickness; PA, primary amenorrhea; PWV, pulse-wave velocity; TS, Turner syndrome.
Received March 28, 2005.
Accepted June 17, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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