Turner syndrome (TS) is a chromosomal disorder; however, little is known about the exercise tolerance of patients with this syndrome. The aim of the present study was to measure the maximal aerobic capacity and cardiac function using cardiopulmonary exercise testing and lung function tests and to evaluate the cardiac parameters using echocardiography in patients with TS and control subjects. A total of 50 women with TS (mean age 21.3 ± 8.5 years) and 56 age-matched controls (mean age 21.1 ± 3.7 years) were enrolled from the Pediatric Department of “Sapienza” University of Rome and underwent cardiopulmonary exercise testing, lung function testing, and echocardiography. The maximal oxygen uptake was lower in the patients with TS than in the controls (28.4 ± 4.0 vs 35.6 ± 6.2 ml/min/kg; p <0.0001). Also, the forced expiratory volume in 1 second, expressed as a percentage of the predicted value, was greater in the patients with TS than in the controls (116.2 ± 15.2% vs 102.8 ± 4.8%, p <0.0001). The patients with TS had a smaller left ventricle than did the controls. Tissue Doppler imaging revealed subclinical systolic and diastolic dysfunction in the left ventricle in those with TS but not in the controls. The left ventricular mass index was greater in the patients with TS than in the controls (38.6 ± 9.3 vs 27.2 ± 4.5 g/m 2.7 , p <0.0001). In conclusion, the patients with TS had a lower maximal aerobic capacity and exercise tolerance than did the controls. The anatomic and functional cardiac aspects were peculiar to those with TS and might represent a specific cardiac phenotype.
Turner syndrome (TS) is a chromosomal disorder with a complete or partial absence of the X chromosome in some or all cells. It affects approximately 1 in 2,000 female live births. The prevalent features of TS are short stature, generally associated with gonadal dysgenesis, cardiovascular and renal malformations, skeletal abnormalities, thyroid pathologic features, and motor coordination impairment. Aortic coarctation and bicuspid aortic valve, with a high risk of aortic dilation and dissection, have been the most common cardiovascular malformations. Recent studies have found electrocardiographic and autonomic abnormalities and diastolic dysfunction in subjects with TS, suggesting more extensive involvement of the cardiovascular system. However, few studies have evaluated the pulmonary function at rest or the exercise tolerance of patients with TS during submaximal exercise, and no cardiopulmonary exercise test results have yet been reported. The aim of our study was to evaluate the exercise tolerance, as measured by the maximal oxygen uptake (VO 2 max) and exercise time, and cardiac function in patients with TS compared to healthy subjects using cardiopulmonary exercise testing, lung function tests, and echocardiographic study.
Methods
From September 2007 to February 2010, 50 young women with karyotype-proven TS were consecutively enrolled from the Pediatric Department of “Sapienza” University of Rome. Of these 50 subjects, 28 had the 45,X karyotype; 1 had 45,X/46,XX; 11 had 45,X/46,Xr–45,X/46,Xi(Xq)–45,X/46,Xdel(X)–45,X/46Xiso(X)–45,X/46,Xidic(X)–45,Xinv(q)/46X,i(X); 5 had 46,Xdel(Xp),46X,idic(X),46,Xiso(X); 3 had 45,X/46,XY; and 2 had 45,X/47,XXX.
A total of 56 age-matched healthy women with a normal karyotype and a sedentary lifestyle were studied as the control group. Their age and anthropometric parameters are listed in Table 1 . All subjects gave written informed consent, and the scientific ethics committee approved the protocol.
| Variable | Turner syndrome (n = 50) | Controls (n = 56) | p Value |
|---|---|---|---|
| Age (years) | 21.3 ± 8.5 (7.2–38.9) | 21.1 ± 3.7 (11.8–27.8) | NS |
| Height (cm) | 145.1 ± 12.7 (110–160) | 162.8 ± 6.2 (146–174) | <0.0001 |
| Weight (kg) | 48.2 ± 12.1 (17–65.5) | 51.8 ± 5.8 (39.5–69) | <0.05 |
| Body mass index (kg/m 2 ) | 22.4 ± 3.3 (14.1–29.1) | 19.6 ± 1.9 (16.2–25.8) | <0.0001 |
All the patients enrolled in the present study underwent a medical history and physical examination. None of the 50 patients included in the protocol study had presented with contraindications to exercise testing. Any patients with TS and significant enlargement of the aortic root previously demonstrated by echocardiography and/or magnetic resonance imaging were excluded. A standardized pediatric questionnaire was administered to all patients to quantify the time dedicated within 1 week to physical activity. All subjects (TS and controls) were young women with a sedentary lifestyle and similar hours of physical activity weekly (TS 1.6 ± 0.9 hours/week; controls 1.5 ± 0.8 hours/week; p = NS).
Spirometry was performed and the cardiopulmonary parameters were measured using Cosmed Quark PFT4 ergo (Rome, Italy). All patients underwent spirometry testing according to the American Thoracic Society/European Respiratory Society Task Force guidelines, before and after the exercise test to determine the following parameters: forced vital capacity, forced expiratory volume first second (FEV 1 ), ratio between the FEV 1 and forced vital capacity, peak expiratory flow, and forced expiratory flow at 50% of vital capacity. The results are expressed as percentages of the normal values compared to the predicted reference equations obtained by algorithms according to age, gender, and body size (height and weight).
Each patient performed static lung volume testing according to the American Thoracic Society/European Respiratory Society Task Force using the nitrogen washout method before exercise testing to obtain the total lung capacity and functional residual capacity. The maximal percentage of decrease in FEV 1 was calculated using the following equation: (pre-exercise FEV 1 − lowest FEV 1 after exercise)/pre-exercise FEV 1 × 100. Those who reached a percentage of decrease in FEV 1 ≥12% were considered to have bronchial hyperreactivity.
A 12-lead electrocardiogram (Norav Medical, version 4.5.7, Norav Medical Ltd., Israel) with the subject supine and at rest was obtained and used as the “standard” electrocardiogram tracing before the exercise test. All electrocardiograms were reviewed by the same observer, who was unaware of the subject allocation (TS vs controls). The QT interval, as corrected for heart rate (QTc), was calculated according to Bazzett’s formula and compared to the generally accepted upper normal limit for QTc (≤440 ms). All subjects performed a maximal incremental exercise on a treadmill (Bruce protocol) that consisted of increasing the speed and slope every 3 minutes until exhaustion and a heart rate of ≥85% of the maximal heart rate (calculated using the formula 220 − age in years) was reached. At the maximal exercise effort, the young women showed breathlessness (32.0% of those with TS and 21.4% of the controls) and pain in the leg muscles (12.0% of those with TS and 7.1% of the controls). The systolic and diastolic blood pressure was measured, with the subjects in a sitting position and every 3 minutes during the exercise test by the same physician. The gas analyzers and flow transducers were calibrated before each test. During exercise, the subjects were connected by a face mask to a breath-by-breath analyzer of carbon dioxide and oxygen to measure the following parameters: minute ventilation, respiratory frequency, tidal volume, oxygen uptake, carbon dioxide output, ratio of carbon dioxide output to oxygen uptake per unit of time (respiratory exchange ratio), and total exercise time in minutes. The VO 2 max was defined as the greatest level of oxygen uptake reached during the maximum exercise test. The anaerobic threshold was determined using the V-slope method and the ventilatory equivalent for carbon dioxide. The anaerobic threshold was expressed as a percentage of the measured VO 2 max. The oxygen pulse was obtained from the ratio of the VO 2 max and heart rate.
All 50 patients with TS and the 56 age-matched healthy women used as controls underwent transthoracic echocardiography, performed by a single pediatric cardiologist. The equipment used was the Philips Sonos 5500 (Philips, Andover, Massachusetts), with a 4-MHz phased-array transducer. Of the 50 patients with TS, 11 (22%) had a bicuspid aortic valve, 9 (18%) had mitral valve prolapse, 3 (6%) had partial anomalous pulmonary venous return involving one pulmonary vein from the left upper lobe to the left brachiocephalic vein, 2 (4%) had undergone surgical repair of coarctation of the aorta during infancy, and 1 (2%) had persistent left superior vena cava. None of the patients had hemodynamically significant mitral or aortic regurgitation or aortic stenosis. Neither of the subjects with previous coarctation repair had a residual systolic pressure gradient >10 mm Hg at rest detected by continuous wave Doppler. The left ventricular internal diameter in diastole and systole, interventricular septum diastolic thickness, and left ventricle posterior wall diastolic thickness were measured according to the criteria of the American Society of Echocardiography. The aortic root diameters were measured in the 2-dimensional mode at 4 levels (aortic annulus, sinuses of Valsalva, sinotubular junction, and proximal part of the ascending aorta) according to the latest 2005 American Society of Echocardiography chamber quantification guidelines. The ejection fraction and fractional shortening were calculated using M-mode imaging to assess the global systolic function of the left ventricle. After these conventional echocardiographic evaluations, tissue pulsewave Doppler imaging (TDI) was performed to assess the systolic and diastolic function of the left ventricle. TDI was performed in the 4-chamber view, placing the Doppler sample volume in the myocardium at the lateral border of the mitral annulus. The following pulsewave TDI indexes were obtained: peak velocity of systolic excursion of the lateral mitral annulus (S m ); peak velocities of early and late diastolic excursion of the lateral mitral annulus (E m and A m , respectively), and their ratio (E m /A m ). The left ventricular mass was calculated using the Devereux equation. The left ventricular mass index was determined by dividing the left ventricular mass in grams by the height in meters to the power of 2.7. All measurements were determined from the average of 3 consecutive cardiac cycles.
All statistical calculations were performed using the Statistical Package for Social Sciences for Windows, version 13.0 (SPSS, Chicago, Illinois). The significance of differences between the 2 study groups was tested using Student’s 2-tailed unpaired t test. The results are presented as the mean ± SD and range. Linear regression tests were used to search for relations between the TDI parameters of systolic and diastolic left ventricle function (S m , E m ) and VO 2 max and oxygen pulse in the patients with TS and the controls. To determine whether a statistically significant difference was present between the regression lines of those with TS and the controls, we compared the slopes and intercepts of the curves using the global F test (analysis of variance). The significance level was set at p ≤0.05.
Results
In all subjects, the heart rate and blood pressure measured at rest were normal for gender, age, and height according to the National High Blood Pressure Education Program Working Group. However, the diastolic blood pressure and heart rate were significantly greater statistically in the TS subjects than in the controls (systolic blood pressure 116.9 ± 7.8 mm Hg for those with TS vs 116.2 ± 6.6 mm Hg for the controls, p = NS; diastolic blood pressure 74.2 ± 7.5 mm Hg for those with TS vs 69.1 ± 4.2 mm Hg the controls, p <0.0001; heart rate 94.8 ± 7.4 beats/min for those with TS vs 73.8 ± 4.2 beats/min for the controls, p <0.0001). The QTc interval was significantly longer in the patients with TS than in the controls (422 ± 24 vs 409 ± 20 ms, p = 0.005).
The mean values of the static and dynamic lung flows and volumes, expressed as absolute values, in the controls were significantly greater than in those with TS, except for the functional residual capacity and total lung capacity. In contrast, the same spirometric parameters, expressed as percentages of the predicted values, were significantly greater in those with TS than in the controls, with the exception of the peak expiratory flow and the forced expiratory flow at 50% of vital capacity ( Table 2 ).
| Variable | Measured Values | Percentage of Predicted | ||||
|---|---|---|---|---|---|---|
| Turner Syndrome (n = 50) | Controls (n = 56) | P Value | Turner Syndrome (n = 50) | Controls (n = 56) | p Value | |
| Forced vital capacity (L) | 3.06 ± 0.75 (1.16–4.34) | 3.78 ± 0.61 (2.42–4.29) | <0.0001 | 114.7 ± 18.3 (88.8–170.2) | 106.1 ± 5.5 (94–119.5) | <0.001 |
| Forced expiratory volume in 1 second (L) | 2.81 ± 0.71 (1.15–4.24) | 3.26 ± 0.68 (2.10–4.16) | <0.001 | 116.2 ± 15.2 (89.3–153.9) | 102.8 ± 4.8 (92–110.8) | <0.0001 |
| Forced expiratory volume in 1 second/forced vital capacity × 100 | 91.7 ± 6.0 (78.4–99.7) | 86.2 ± 5.4 (77.4–96.5) | <0.0001 | — | — | — |
| Peak expiratory flow (L/s) | 5.71 ± 1.55 (2.55–8.55) | 7.23 ± 1.69 (4.32–9.14) | <0.0001 | 109.9 ± 22.0 (87.5–131.7) | 105.6 ± 4.9 (91.4–115.8) | NS |
| Forced expiratory flow 50% of vital capacity (L/s) | 3.76 ± 1.15 (1.24–6.32) | 4.63 ± 1.29 (1.89–6.84) | <0.0001 | 103.2 ± 23.7 (59.1–168.1) | 101.6 ± 5.8 (85.4–109.5) | NS |
| Functional residual capacity (L) | 2.59 ± 1.40 (1.51–4.34) | 2.80 ± 1.62 (1.68–4.65) | NS | 138.7 ± 71.8 (58.2–198.0) | 104.5 ± 6.5 (95.3–118.3) | <0.0001 |
| Total lung capacity (L) | 4.61 ± 1.60 (2.11–5.87) | 5.12 ± 1.83 (2.43–6.12) | NS | 122.4 ± 36.7 (48.1–187.3) | 103.2 ± 7.1 (95.3–118.3) | <0.0001 |
None of the women (TS or controls) studied showed bronchial hyperreactivity after exercise testing. The percentage of the decrease in FEV 1 calculated for all subjects was <12% (1.8 ± 2.6% for those with TS vs 2.2 ± 3.1% for the controls, p = NS).
The mean values of the cardiopulmonary parameters measured at maximum workload in all subjects are listed in Table 3 . Those with TS had mean values of minute ventilation/kg, respiratory frequency, VO 2 max, oxygen pulse, and exercise time that were significantly lower than those of the controls. In contrast, the mean values of the tidal volume/kg were significantly greater statistically than those for the controls, and the mean respiratory exchange ratio, heart rate, and anaerobic threshold (percentage of measured VO 2 max) were similar in both groups. The blood pressure at maximum exercise testing were normal in all subjects, although the systolic blood pressure was significantly greater statistically in the controls than in those with TS, according to the American Heart Association Council statement. Compared to healthy subjects, the patients with TS had a significantly reduced left ventricular internal diameter in diastole and a significantly increased interventricular septum diastolic thickness. The left ventricular internal diameter in systole and left ventricle posterior wall diastolic thickness did not show any significant differences. A comparison of the echocardiographic data regarding the aortic root diameters showed similar values in both groups. The ejection fraction and fractional shortening were also similar ( Table 4 ). Moreover, in those with TS, the S m and E m were significantly reduced, and the A m and E m /A m ratios were similar in both groups. The left ventricular mass index was significantly greater in the women with the TS than in the healthy subjects. We observed a significant correlation between the VO 2 max/kg and TDI parameters (E m and S m ; Figures 1 and 2 ). We found a significant difference in the regression lines of the 2 groups between the VO 2 max/kg and TDI parameters (VO 2 max/kg and S m , F = 7.03; p <0.001; VO 2 max/kg and E m , F = 14.3; p <0.0001).
| Variable | Turner Syndrome (n = 50) | Controls (n = 56) | p Value |
|---|---|---|---|
| Minute ventilation (ml/min/kg) | 978.3 ± 308.8 (533–1,835) | 1246.9 ± 297.0 (650–1,967) | <0.0001 |
| Respiratory frequency (breaths/min) | 37.8 ± 9.8 (23.4–67.8) | 52.4 ± 6.8 (36–65.5) | <0.0001 |
| Tidal volume (ml/kg) | 26.3 ± 5 (15.7–37.1) | 23.7 ± 4.5 (13.3–34.5) | <0.008 |
| Maximal oxygen uptake (ml/min/kg) | 28.4 ± 4.0 (22.1–45.4) | 35.6 ± 6.2 (25.5–49.6) | <0.0001 |
| Respiratory exchange ratio | 1.16 ± 0.09 (1.11–1.27) | 1.18 ± 0.08 (1.11–1.29) | NS |
| Heart rate (beats/min) | 184.8 ± 12.9 (168–203) | 189.3 ± 15.7 (169–204) | NS |
| Oxygen pulse (ml/min/beat) | 7.5 ± 1.3 (4.3–11.1) | 9.4 ± 1.4 (6.7–11.9) | <0.0001 |
| Exercise Time (min) | 9.1 ± 1.4 (5–12.3) | 11.0 ± 2.1 (8–15.7) | <0.0001 |
| Anaerobic threshold (%) | 53.3 ± 15.5 (29–84) | 51.5 ± 12.7 (38–78) | NS |
| Systolic blood pressure (mm Hg) | 144.1 ± 12.4 (120–180) | 149.7 ± 10.6 (130–180) | <0.01 |
| Diastolic blood pressure (mm Hg) | 65.9 ± 11.3 (40–85) | 63.0 ± 8.6 (40–75) | NS |
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