A Prospective Study of Lipids in Adult Women With Turner Syndrome.

Context: Turner syndrome (TS) is a rare genetic syndrome with an increased mortality, mainly attributed to cardiovascular disease. Objective: This work aimed to investigate and correlate the lipid profile in adult women with TS to clinical characteristics. Methods: A 12-year prospective cohort study, including 4 study visits, was conducted at a specialist hospital. A total of 102 women with TS qualified for inclusion. Excluding missing variables and participants lost to follow-up, 86 women (mean age 38.1 years; range, 18.4-62.1 years) were included in this study. Fifty-three women completed the study. Repeated-measurement analysis was performed, using total cholesterol (Total-C), low-density lipoprotein (LDL), triglycerides (TGs), and high-density lipoprotein (HDL) as outcome variables and age, karyotype, body mass index (BMI), treatment with statins, antidiabetics, and hormone replacement therapy as explanatory variables. Principal component analysis (PCA) and partial least squares (PLS) analysis were performed at the first study visit. Results: Hyperlipidemia was present in 30% of the TS cohort. Total-C increased with age (0.12 mmol/L/y; P = .016). LDL (P = .08), TGs (P = .14), and HDL (P = .24) were not associated with age. BMI significantly increased total-C (0.19 mmol/L/kg/m2; P = .006), LDL (0.63 mmol/L/kg/m2; P < .001), and TGs (0.80 mmol/L/kg/m2; P < .001) and decreased HDL (-0.59 mmol/L/kg/m2; P < .001). PCA and PLS analysis found correlations between weight and BMI and total-C, LDL, and TGs. Conclusion: Hyperlipidemia is more prevalent in adult women with TS across adulthood compared to the background population. Total-C, LDL, TGs, and HDL were significantly associated with BMI characterizing the atherogenic profile in adult women with TS.

The TGFß system and TIMP1 and 3 genotypes in Turner syndrome-Relation with aortic congenital malformations.

OBJECTIVE: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk. DESIGN, PATIENTS, PARTICIPANTS AND MEASUREMENTS: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFß), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease. RESULTS: TS participants had lower TGFß1 and TGFß2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFß1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFß1 and TGFß2 levels in TS. CONCLUSION: TGFß and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants.

Dual-source computed tomography coronary artery imaging in children.

Computed tomography (CT) has a well-established diagnostic role in the assessment of coronary arteries in adults. However, its application in a pediatric setting is still limited and often impaired by several technical issues, such as high heart rates, poor patient cooperation, and radiation dose exposure. Nonetheless, CT is becoming crucial in the noninvasive approach of children affected by coronary abnormalities and congenital heart disease. In some circumstances, CT might be preferred to other noninvasive techniques such as echocardiography and MRI for its lack of acoustic window influence, shorter acquisition time, and high spatial resolution. The introduction of dual-source CT has expanded the role of CT in the evaluation of pediatric cardiovascular anatomy and pathology. Furthermore, technical advances in the optimization of low-dose protocols represent an attractive innovation. Dual-source CT can play a key role in several clinical settings in children, namely in the evaluation of children with suspected congenital coronary artery anomalies, both isolated and in association with congenital heart disease. Moreover, it can be used to assess acquired coronary artery abnormalities, as in children with Kawasaki disease and after surgical manipulation, especially in case of transposition of the great arteries treated with arterial switch operation and in case of coronary re-implantation.

Golden ratio stack of spirals for flexible angiographic imaging: Proof of concept in congenital heart disease.

PURPOSE: In this study, a golden ratio stack of spiral (GRASS) sequence that used both golden step and golden angle ordering was implemented. The aim was to demonstrate that GRASS acquisitions could be flexibly reconstructed as both cardiac-gated and time-resolved angiograms. METHODS: Image quality of time-resolved and cardiac-gated reconstructions of the GRASS sequence were compared to 3 conventional stack of spirals (SoS) acquisitions in an in silico model. In 10 patients, the GRASS sequence was compared to conventional breath hold angiography (BH-MRA) in terms of image quality and for vessel measurement. Vessel measurements were also compared to cine images. RESULTS: In the cardiac-gated in silico model, the image quality of GRASS was superior to regular and golden-angle with regular step SoS approaches. In the time-resolved model, GRASS image quality was comparable to the golden-angle with regular step technique and superior to regular SoS acquisitions. In patients, there was no difference in qualitative image scores between GRASS and BH-MRA, but SNR was lower. There was good agreement in vessel measurements between the GRASS reconstructions and conventional MR techniques (BH-MRA: 29.8 ± 5.6 mm, time-resolved GRASS-MRA: 29.9 ± 5.4 mm, SSFP diastolic: 29.4 ± 5.8 mm, cardiac-gated GRASS-MRA diastolic: 29.5 ± 5.5 mm, P > 0.87). CONCLUSION: We have demonstrated that the GRASS acquisition enables flexible reconstruction of the same raw data as both time-resolved and cardiac-gated volumes. This may enable better interrogation of anatomy in congenital heart disease.

Clinical and pathophysiological aspects of bicuspid aortic valve disease.

A bicuspid aortic valve is not only a common congenital heart defect but also an enigmatic condition that can cause a large spectrum of diseases, such as aortic valve stenosis and severe heart failure in newborns whereas aortic dissection in adults. On the contrary, a bicuspid aortic valve can also occur with normal function throughout life and never need treatment. Numerous genetic mechanisms are involved in the abnormal cellular functions that may cause abnormal development of the aortic valve during early foetal life. As several chromosomal disorders are also associated with a bicuspid valve, there does not appear to be an apparent common trigger to the abnormal development of the aortic valve. The clinical care of the bicuspid aortic valve patient has been changed by a significant body of evidence that has improved the understanding of the natural history of the disease, including when to best intervene with valve replacement and when to provide prophylactic aortic root surgery. Moreover, as bicuspid valve disease is also part of various syndromes, we can identify high-risk patients in whom a bicuspid valve is much more unfavourable than in the normal population. This review provides an overview of all aspects of the bicuspid aortic valve condition and gives an updated perspective on issues from pathophysiology to clinical care of bicuspid aortic valve disease and associated aortic disease in asymptomatic, symptomatic, and pregnant patients, as well as our viewpoint on population screening.

Low myocardial glucose uptake in Turner syndrome is unaffected by growth hormone: a randomized, placebo-controlled FDG-PET study.

BACKGROUND: An unfavourable cardiovascular and metabolic phenotype causes threefold excess mortality in Turner syndrome (TS), and perturbed cardiac substrate metabolism is increasingly recognized as a common component of cardiovascular and metabolic diseases. We therefore hypothesized that myocardial glucose uptake (MGU) is reduced in TS and that growth hormone (GH) treatment improves MGU. To this end, this controlled trial elucidates MGU in TS and the impact of 6 months of growth hormone treatment on MGU. METHODS AND RESULTS: Women with TS (n = 9) were examined at baseline, sequentially treated with either Norditropin(®) SimpleXx or placebo and re-examined after 6 months. MGU and myocardial blood flow (MBF) were measured using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) during a hyperinsulinaemic euglycaemic clamp (at baseline and 6 months). Blood pressure measurement, blood sampling, echocardiography and dual energy X-ray absorptiometry scan were also performed. Age-matched female controls (n = 9) were examined once. Baseline MGU was reduced in TS (0.24 ± 0.08 vs. 0.36 ± 0.13 µmol/g/min in controls; P = 0.036) despite similar insulin sensitivity (whole body glucose uptake (M-value): 9.69 ± 1.86 vs. 9.86 ± 2.58 mg/(min*kg) in controls; P = 0.9). Six months of GH carried no impact on MGU (0.25 ± 0.08 vs. 0.26 ± 0.12 µmol/g/min in the placebo group; P = 0.8). Plasma glucose, low-density cholesterol and triglycerides increased, while M-value and exercise capacity decreased during 6 months of GH treatment. CONCLUSION: MGU is reduced in TS despite normal insulin sensitivity. GH treatment does not alter MGU despite decreased whole body insulin sensitivity. A perturbed cardiac glucose uptake appears to be a feature of TS.

Osteoprotegerin in Turner syndrome - relationship to aortic diameter.

BACKGROUND: Cardiovascular disease is a cardinal trait of Turner syndrome (TS), causing half of the threefold excess mortality. As osteoprotegerin (OPG) is a potential biomarker of cardiovascular disease, this cross-sectional and prospective study aimed at elucidating OPG levels in TS and its relationship to aortic diameter as well as validated cardiovascular risk markers. METHODS: Adult women with TS (n = 99) were examined thrice (mean follow-up 4·7 ± 0·5 years), and 68 age-matched healthy female controls were examined once. Aortic diameter was assessed by cardiovascular magnetic resonance. Twenty-four-hours blood pressure monitoring and biochemical assessments were also performed. RESULTS: Osteoprotegerin levels (median with range) were lower in TS (777 [326-10 569] ng/l) compared with controls (979 [398-1987] ng/l; P < 0·05) and did not change during follow-up. The OPG concentration was higher among women with TS older than 50 years of age (996 [542-4996] vs 756 [326-10 569] ng/l; P < 0·05) with a trend towards a higher OPG in TS who were on antihypertensive medication (938 [490-2638] vs 752 [326-10 569] ng/l; P = 0·09). Contrary to controls, OPG levels correlated with BSA-indexed aortic diameter (r = 0·31-0·45; P < 0·05), age (r = 0·29; P < 0·05) and high-sensitivity C-reactive protein (r = 0·23; P = 0·02) and inversely with BSA (r = -0·20; P < 0·05), weight (r = -0·23; P < 0·05) and plasma oestradiol levels (r = -0·34; P < 0·05). CONCLUSION: Levels of OPG are lower in TS and correlate with aortic diameter, age, BSA, weight and oestradiol in TS, but not controls. Future studies are needed to assess whether OPG may serve as a biomarker of aortic or cardiovascular disease in TS.

Clinical care of adult Turner syndrome--new aspects.

Turner syndrome (TS) is characterized by numerous medical challenges during adolescence and adulthood. Puberty has to be induced in most cases, and female sex hormone replacement therapy (HRT) should continue during adult years. These issues are normally dealt with by the paediatrician, but once a TS female enters adulthood it is less clear who should be the primary care giver. Morbidity and mortality is increased, especially due to the risk of dissection of the aorta and other cardiovascular diseases, as well as the risk of type 2 diabetes, hypertension, osteoporosis, thyroid disease and other diseases. The proper dose of HRT with female sex steroids has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. The transition period from paediatric to adult care seems to be especially vulnerable and the proper framework for transition has not yet been established. Likewise, no framework is in place for continuous follow-up during adult years in many countries. Today, most treatment recommendations are based on expert opinion and are unfortunately not evidence based, although more areas, such as growth hormone and oxandrolone treatment for increasing height, are becoming well founded. Osteoporosis, diabetes, both type 1 and 2, hypothyroidism, obesity and a host of other endocrine diseases and conditions are seen more frequently in TS. Prevention, intervention and proper treatment is only just being recognized. Hypertension is frequent and can be a forerunner of cardiovascular disease. The description of adult life with TS has been broadened and medical, social and psychological aspects are being added at a compelling pace. Proper care during adulthood should be studied and a framework for care should be in place, since most morbidity potentially is amenable to intervention. In summary, TS is a condition associated with a number of diseases and conditions which need the attention of a multi-disciplinary team during adulthood.

Left ventricular hypertrophy in Turner syndrome: a prospective echocardiographic study.

BACKGROUND: Cardiovascular risk stratification in Turner syndrome (TS) is difficult. Increased left ventricular mass associates with an adverse prognosis in several settings, and this study aimed to elucidate this risk marker in relation to metabolic and cardiovascular status in TS. METHODS: An echocardiographic follow-up study (4.8 years) of 82 adult females with TS. Left ventricular mass was the primary outcome parameter. Metabolic status (glucose, Hemoglobin A1c, lipids), aortic valve function and morphology, and 24-hour ambulatory blood pressure were secondary outcome parameters. Healthy age-matched females served as baseline controls (n = 55). RESULTS: Left ventricular mass was increased in TS (TS vs. controls: 88 ± 21 g/m(2) vs. 77 ± 12 g/m(2), P < 0.05). More participants were treated for hypertension at follow-up (32% at baseline vs. 55% at follow-up). This coincided with a reduction of left ventricular mass in TS (84 ± 20 g/m(2) at follow up, P < 0.05) and favorable remodeling with a contrasting increase in left atrial size. In a baseline multiple regression model, left ventricular mass (r(2) = 0.28, P < 0.05) increased with body surface area, age and the presence of a bicuspid aortic valve. In another model, left ventricular mass increased with blood pressure, ongoing estrogen treatment and body surface area (r(2) = 0.26, P < 0.05). No single factor reached statistically significant levels for prediction of prospective left ventricular mass changes. CONCLUSION: The increased left ventricular mass in TS was associated with aortic valve disease, age, hypertension, physical stature and metabolic status. During follow-up left ventricular mass was only slightly reduced along with blood pressure, whereas the diastolic dysfunction did not seem to improve.

Socioeconomic parameters and mortality in Turner syndrome.

BACKGROUND: Turner syndrome (TS) is characterized by hypogonadism, short adult height, increased morbidity and mortality, contrasted by self-reported normal quality of life and perception of health. Small studies have indicated a similar level of education compared with the background population. AIM: To study the socioeconomic profile in TS and the impact of these factors on mortality. MATERIALS AND METHODS: Register study using Danish nationwide registries. Nine hundred and seventy-nine TS females and 94,850 controls were included. Information concerning cohabitation, motherhoods, level of education (bachelor degree), income, retirement, and death were obtained. One hundred and three TS and 5989 controls died during the study period. For the socioeconomic parameters, median age at first relevant episode was calculated. Income was analyzed using conditional logistic regression and the other parameters using Cox regression. RESULTS: In comparison with controls, TS had significantly fewer partnerships (hazard ratio (HR): 0.45), fewer motherhoods (HR: 0.18), and retired earlier (HR: 1.8). After the diagnosis of TS, the risk of retiring was increased. Educational attainment (HR: 1.0) as well as risk of unemployment was similar. Before the age of 30, low income was significantly more frequent; hereafter, it was similar to controls. Mortality was significantly increased (HR: 2.9) and slightly lower after adjustment for cohabitation and education (HR: 2.7). CONCLUSIONS: A divergent socioeconomic profile is apparent, with a reduced proportion of TS persons finding a partner and becoming mothers. The educational level was similar to controls. The increased mortality in TS was not materially affected after adjustment for cohabitation and education.

Abnormalities of the major intrathoracic arteries in Turner syndrome as revealed by magnetic resonance imaging.

BACKGROUND: Ectatic aortopathy and arterial abnormalities cause excess morbidity and mortality in Turner syndrome, where a state of vasculopathy seemingly extends into the major head and neck branch arteries. OBJECTIVE: We investigated the prevalence of abnormalities of the major intrathoracic arteries, their interaction with arterial dimensions, and their association with karyotype. DESIGN: Magnetic resonance imaging scans determined the arterial abnormalities as well as head and neck branch artery and aortic dimensions in 99 adult women with Turner syndrome compared with 33 healthy female controls. Echocardiography determined aortic valve morphology. RESULTS: In Turner syndrome, the relative risk of any congenital abnormality was 7.7 (p = 0.003) and 6.7 of ascending aortic dilation (p = 0.02). A bovine aortic arch was seen in both Turner syndrome and controls. Other abnormalities were only encountered in Turner syndrome: elongated transverse aortic arch (47%), bicuspid aortic valve (27%), aortic coarctation (13%), aberrant right subclavian artery (8%), and aortic arch hypoplasia (2%). The innominate and left common carotid arteries were enlarged in Turner syndrome (p < 0.001). Significant associations were first, bicuspid aortic valve with aortic coarctation, elongated transverse aortic arch, and ascending aortic dilation; second, aortic coarctation with elongated aortic arch and descending aortic dilation; third, 45,X with aortic coarctation, elongated transverse aortic arch and ascending aortic dilation; and fourth, branch artery dilation with bicuspid aortic valve, aortic coarctation, elongated transverse aortic arch and 45,X. CONCLUSION: An increased risk of arterial abnormalities, aortic dilation, and enlargement of the branch arteries was found in Turner syndrome without distinct patterns of co-segregation.

Repeated spontaneous pregnancies in 45,X Turner syndrome.

BACKGROUND: Spontaneous pregnancy rarely occurs in women with Turner syndrome, and poor maternal outcomes are prominent in these women. CASES: We report two women with 45,X Turner syndrome who had a total of four spontaneous pregnancies. Maternal and fetal outcomes were good despite maternal comorbidities. Cesarean deliveries were performed in two of the pregnancies because of aortic dilatation and fetopelvic disproportion. Both cases were initially diagnosed as primary amenorrhea (absent pubarche and menarche with serological hypogonadism). CONCLUSION: Repeated spontaneous pregnancies occur in women with 45,X Turner syndrome. Poor maternal outcome is not the rule.

Turner syndrome and clinical treatment.

BACKGROUND: Turner syndrome (TS) is a genetic disorder associated with abnormalities of the X chromosome, occurring in about 50 per 100,000 liveborn girls. TS is usually associated with reduced adult height, gonadal dysgenesis and thus insufficient circulating levels of female sex steroids leading to premature ovarian failure and infertility. The average intellectual performance is within the normal range. New insight into genetics, epidemiology, cardiology, endocrinology and metabolism from a number of recent studies will be included in this review. SOURCES OF DATA: For this review we concentrated on all papers published on TS with special emphasis on the most recent literature. Also papers relating to cardiology, especially aortic dissection, paediatrics and the effects of estradiol in other conditions were considered. The main source was PubMed and the major endocrinology and cardiology journals. AREAS OF AGREEMENT: Treatment with growth hormone (GH) during childhood and adolescence allows a considerable gain in adult height. SHOX deficiency explains some of the phenotypic characteristics in TS, principally short stature. Puberty has to be induced in most cases, and female sex hormone replacement therapy (HRT) is given during adult years. Morbidity and mortality is increased, especially due to the risk of dissection of the aorta and other cardiovascular (CV) diseases, as well as the risk of type 2 diabetes, osteoporosis and thyroid disease. AREAS OF CONTROVERSY: The proper dose of HRT with female sex steroids has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. In most countries it seems that the transition period from paediatric to adult care is especially vulnerable and the proper framework for transition has not been established. Today, most treatment recommendations are based on expert opinion and are unfortunately not evidence based, although more areas, such as GH treatment for increasing height, are well founded. GROWING POINTS: The description of adult life with TS has been broadened and medical, social and psychological aspects are being added at a compelling pace. AREAS TIMELY FOR DEVELOPING RESEARCH: Proper care during adulthood should be studied, since most morbidity potentially is amenable to proper care. Especially, interventional strategy and follow-up with respect to congenital CV malformations, as well as secondary CV disease, have to be developed and new treatment algorithms have to be studied. In summary, TS is a condition associated with a number of diseases and conditions, which need the attention of a multi-disciplinary team.