Lymphedema, Low-grade Inflammation and the Vasculature in Turner Syndrome

Cardiovascular Diseases Clinical Trial

— TSCOR_V  

Official title:

Lymphedema, Low-grade Inflammation and the Vasculature in Turner Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06325618
• Other study ID #: 1-10-72-138-23
• Status: Recruiting
• Start date: January 8, 2024
• Est. completion date: August 2027

Study information

• Verified date: January 2024
• Source: University of Aarhus
• Contact: Line Balsby, MD
• Phone: +4520461203
• Email: libals[@]clin.au.dk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

100 women with karyotype verified TS, previously examined at 4 study visits during a 19-year period will be asked to participate in a 5th study visit. Healthy age-matched females will be included as controls in a ratio 2:1.

The aim is to examine and quantify the cardiovascular and lymphatic system in women with TS. The investigators will study a possible causal mechanism between the known pathologic phenotype and alterations in these systems to understand, prevent or treat the life-threatening complications in TS.

Description:

Background:

Patients with Turner syndrome (TS) are at risk of many complications during childhood, adolescence, and adulthood, including reduced final height, estrogen deficiency, infertility, lymphedema, ischemic heart disease, aortic dilation and dissection, congenital heart defect, hypertension, stroke, and autoimmune diseases in general.

The aim of this study is to evaluate the lymphatic and cardiovascular system in a cohort of adult women with TS to elucidate any defects, abnormalities or dysfunctions that may explain the myriad of complications related to TS.

Hypotheses:

1. Both the lymphatic and cardiovascular system are affected in TS with alterations in both anatomy, flow, and function.

2. Changes in the lymphatic system are more prevalent than previously assumed, affecting both central and peripheral lymphatic vessels.

3. Changes in lymphatic transportation and development of cardiovascular malformations occur simultaneously in early fetal life, thus disease in either system may interplay with malfunctions in the other.

4. The vascular structure in both lymph- and cardiovascular tissue is affected throughout the body and low-grade inflammation could be a possible factor in this pathogenesis in TS.

5. Changes in the vascular structure affects flow through the systems resulting in increased stress point on vessel walls leading to a possible entry site for a dissection which can be detected through flow analyses.

6. Genomic examination of multiple tissues will help in understanding the underlying genomic background for the congenital malformations seen in TS

Design:

100 women with karyotype verified TS, previously examined at 4 study visits during a 19-year period will be asked to participate in a 5th study visit. Healthy age-matched females will be included as controls in a ratio 2:1.

The lymphatic system will be examined using three different techniques to assess changes in both anatomy and function.

1. The investigators will use Near infrared light to evaluate the lymphatic system and grade dysfunction and detect subclinical lymphedema. Indocyanine Green will be injected subcutaneously in the foot and hand and used to assess the flow 5-60 minutes after injection.

2. A novel MRI technique to illustrate slow moving fluids, thus visualizing lymphatic fluid, will be used to display the contrast between fluids and tissue to view the thoracic duct and more peripheral lymphatic vessels and quantify their function, abnormalities and morphology.

3. A DEXA scan will be performed to calculate and differentiate between subdermal fat and lymphatic drainage or edema.

To evaluate the cardiovascular system, the investigators will use MRI of the heart and aorta to asses both function and morphology to calculate, among others, mean cardiac output, stroke volume, ejection fraction and asses myocardial fibrosis. A novel technique is to use a PET-CT, as this has been associated with atherosclerosis, because it can visualize macrophage rich atherosclerotic plaques and thus detect otherwise undetectable low-grade inflammation and disease in the cardiovascular system which may contribute to the development of cardiovascular complications.

The investigators will also evaluate the flow in the aorta using 4D-flow measurements based on customized MRI protocols to evaluate stress on the aortic wall and analyze the risk of aortic wall rupture and dissection. The potential of this analysis is the possibility to identify patients at high risk and need for medical or surgical intervention at an early stage and thus prevent or minimize this acute life-threatening complication to TS.

Genomic studies: Samples will be taken from multiple tissues (Blood, fat, muscle, skin, buccal swaps, urine) and DNA and RNA will be isolated using standard methodology.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: August 2027
• Est. primary completion date: August 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

• Turner Syndrome

Exclusion Criteria:

• pregnancy

• contraindications for MRI

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Gonadal Dysgenesis
• Inflammation
• Lymphedema
• Syndrome
• Turner Syndrome

Intervention

Other:
• No intervention other than obtaining biopsies
Skin, fat, and muscle biopsies will be obtained

Drug:
• Indocyanine green (ICG)
Indocyanine green will be injected to evaluate the lymphatic system.

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital	Aarhus N

Sponsors (2)

Lead Sponsor	Collaborator
University of Aarhus	Aarhus University Hospital

Country where clinical trial is conducted

Denmark, 

References & Publications (6)

Executive Committee. The Diagnosis and Treatment of Peripheral Lymphedema: 2016 Consensus Document of the International Society of Lymphology. Lymphology. 2016 Dec;49(4):170-84. — View Citation

Hjerrild BE, Mortensen KH, Sorensen KE, Pedersen EM, Andersen NH, Lundorf E, Hansen KW, Horlyck A, Hager A, Christiansen JS, Gravholt CH. Thoracic aortopathy in Turner syndrome and the influence of bicuspid aortic valves and blood pressure: a CMR study. J Cardiovasc Magn Reson. 2010 Mar 11;12(1):12. doi: 10.1186/1532-429X-12-12. — View Citation

Mohanakumar S, Telinius N, Kelly B, Lauridsen H, Boedtkjer D, Pedersen M, de Leval M, Hjortdal V. Morphology and Function of the Lymphatic Vasculature in Patients With a Fontan Circulation. Circ Cardiovasc Imaging. 2019 Apr;12(4):e008074. doi: 10.1161/CIRCIMAGING.118.008074. — View Citation

Mortensen KH, Andersen NH, Gravholt CH. Cardiovascular phenotype in Turner syndrome--integrating cardiology, genetics, and endocrinology. Endocr Rev. 2012 Oct;33(5):677-714. doi: 10.1210/er.2011-1059. Epub 2012 Jun 15. — View Citation

Unno N, Nishiyama M, Suzuki M, Yamamoto N, Inuzuka K, Sagara D, Tanaka H, Konno H. Quantitative lymph imaging for assessment of lymph function using indocyanine green fluorescence lymphography. Eur J Vasc Endovasc Surg. 2008 Aug;36(2):230-236. doi: 10.1016/j.ejvs.2008.04.013. Epub 2008 Jun 4. — View Citation

Yu DX, Ma XX, Zhang XM, Wang Q, Li CF. Morphological features and clinical feasibility of thoracic duct: detection with nonenhanced magnetic resonance imaging at 3.0 T. J Magn Reson Imaging. 2010 Jul;32(1):94-100. doi: 10.1002/jmri.22128. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Grade dysfunction of clinical and subclinical lymphedema using Indocyanine Green Lymphography and Magnetic Resonance Lymphangiography.	Lymphedema will be graded in a total score according to the International Society of Lymphology. The stages are: Stage 0: Subclinical lymphedema. • Stage 1: Early, reversible pitting edema. Stage 2: Irreversible lymphedema. Stage 3: End-stage lymphedema.	3 year
Primary	Detecting low-grade inflammation in Turner Syndrome preforming FDG-PET/CT-scans to locate low grade inflammation.		3 years
Primary	Heat maps of the distribution of wall shear stress in the aorta	Using 4D-flow analyses heat maps of the aorta will be made to illustrate the distribution of wall shear stress.	3 years
Secondary	MRI evaluation and description of vascular abnormalities in Turner Syndrome	Aortic dimensions	3 years
Secondary	Cardiac MRI to evaluate function	Diastolic and systolic function of the left ventricle	3 years
Secondary	Cardiac MRI to evaluate fibrosis of the myocardium	Estimation of myocardial fibrosis	3 years
Secondary	Mapping DNA-methylations patterns in multiple tissues	Mapping DNA-methylation patterns in muscle, skin, fat, blood and urine	3 years
Secondary	Immunologic changes in Turner Syndrome	Measuring blood concentrations of neutrophiles and lymphocytes, to asses neutrophil-to-lymphocyte ratio (NLR).	3 years