NCT06758648

Characterizing the Retinal Microvasculature in Patients with Fabry Disease: a Prospective Observational Study

• Status: Recruiting
• Phase: —
• Study type: Observational
• Enrollment: 63 (estimated)
• Sponsor: Technical University of Munich · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This study aims to gain a deeper understanding of endothelial dysfunction in patients with Fabry disease through a prospective study of the retinal microvasculature and to identify an objective, non-invasive marker to assess disease severity and cardiovascular risk in patients. The main questions addressed are: Do dynamic and static retinal vessel analysis parameters differ from those in healthy individuals? Can these parameters predict cardiovascular and/or Fabry-related events during follow-up? Do these parameters change during follow-up in patients with a non-stable disease?

Detailed description

Fabry disease is a rare genetic disorder characterized by the pathological accumulation of glycosphingolipids, specifically globotriaosylceramide (Gb3), within lysosomes in various cells of the body. This accumulation leads to damage in the cardiovascular, cerebrovascular, and renal systems and is characterized by dysfunction of endothelial cells. This dysfunction results in disturbances in the microcirculation and damage to the supplied systems, leading to a significantly increased cardiovascular risk in patients with Fabry disease. Studies have shown that these patients have a higher risk of premature death due to these risk factors compared to the general population. Early diagnosis and adequate monitoring of enzyme replacement therapy (ERT) are crucial in reducing the risk of cardiovascular events associated with Fabry disease. Currently, LysoGb3 (lysosphingolipid globotriaosylceramide) is considered a biomarker for the diagnosis and monitoring of Fabry disease. Elevated levels of LysoGb3 have been observed in the blood of patients with Fabry disease, and its measurement has been proposed as a diagnostic tool. Additionally, measuring LysoGb3 levels before and after treatment with ERT can be used as a tool to monitor the effectiveness of the therapy in reducing the accumulation of glycosphingolipids in cells and improving symptoms and outcomes in patients with Fabry disease. However, the performance of LysoGb3 as a predictor of cardiovascular events in patients with Fabry disease is not well understood, and more research is needed to confirm its utility in this regard. Therefore, there is a need for additional reliable measurements of the microcirculation that can be performed non-invasively and represent a low burden for participants. The use of non-invasive markers of microcirculation can aid in the early diagnosis and monitoring of Fabry disease, which is crucial for the effective use of ERT. In summary, this study aims to validate new microcirculation markers that can be measured non-invasively in a prospective cohort of patients with Fabry disease and to correlate these markers with established clinical and laboratory parameters. By validating these markers, the study seeks to improve the management of Fabry disease, reduce the burden on participants, and ultimately reduce the incidence of cardiovascular events associated with the disease.

Conditions

• Fabry Disease
• Endothelial Dysfunction
• Microvasculature

Interventions

Type	Name	Description
DIAGNOSTIC_TEST	Dynamic retinal vessel analysis (DVA)	Dynamic retinal vessel analysis (DVA) is an established, non-invasive technique for evaluating the responsiveness of retinal vessels to flickering light stimuli. This technique allows for the measurement of changes in retinal vessel diameter in response to changes in blood flow, providing insight into the microcirculatory function of the retina. In the case of DVA, patients will asked to focus on a needle, and one arteriole and venule diameter were automatically and continuously recorded. Arteriole and venule segments between 0.5 to 1 mm will be analyzed approximately 2-disc diameters away from the optic nerve in a lower-temporal direction. The baseline recording will be 50 seconds, followed by a flickering phase of 20 seconds and then a recovery period of 80 seconds. Three of these cycles were performed. Based on this, we will calculate the percentage of maximum arteriolar (aFID) and venular dilation (vFID) to baseline.
DIAGNOSTIC_TEST	Biochemistry and immune phenotyping	Collection of blood samples from participants for the purpose of performing clinical chemistry analysis. Peripheral blood mononuclear cells (PBMCs) will be isolated from the collected blood samples using standard techniques, such as density gradient centrifugation, and will be analyzed using fluorescence-activated cell sorting (FACS)
DIAGNOSTIC_TEST	Questionnaires (Patient reported outcomes)	This study involves a comprehensive evaluation of life quality, pain, and gastrointestinal (GI) symptoms using a set of established and validated questionnaires. The tools employed include the SF-36 (Short Form-36 Health Survey) to assess overall health-related quality of life across multiple domains, the COMPASS-31 (Composite Autonomic Symptom Score) to evaluate autonomic dysfunction symptoms, and the Brief Pain Inventory (BPI) to measure pain severity and its impact on daily activities. Additionally, the Gastrointestinal Symptom Rating Scale (GSRS) is used to quantify the severity and frequency of GI symptoms, covering dimensions such as reflux, abdominal pain, indigestion, diarrhea, and constipation. Together, these questionnaires provide a multidimensional assessment of the patient's physical, emotional, and symptomatic experiences, allowing for a robust understanding of their health status and quality of life.
DIAGNOSTIC_TEST	Cardio MRI	Cardiovascular magnetic resonance imaging (CMR or cardio MRI) will be utilized in patients with Fabry disease. This imaging technique will enable detailed assessment and monitoring of key cardiac abnormalities, including thickening of the heart walls, left ventricular hypertrophy, and decreased blood flow in the coronary vessels. Additionally, T1 relaxation time measurement will be conducted, offering a non-invasive means to detect myocardial tissue abnormalities such as fibrosis and sphingolipid accumulation, which are hallmarks of Fabry disease. Together, these measures provide a comprehensive evaluation of cardiac structure, function, and tissue characteristics in affected patients.
DIAGNOSTIC_TEST	Optical coherence tomography (OCT)	Optical coherence tomography (OCT) is a non-invasive, high-resolution imaging technique that utilizes low-coherence light to capture cross-sectional images of the ocular fundus. Based on the principle of interferometry, OCT employs low-coherence light, which is scattered by the tissue, to produce detailed, high-resolution images of the retina and its layers. This technology enables precise visualization of the different retinal layers, including the nerve fiber layer, the ganglion cell layer, and the inner and outer plexiform layers. Additionally, OCT can be used to detect and monitor subtle structural changes in the retina, offering critical insights into retinal microarchitecture and potential manifestations of systemic diseases such as Fabry disease.
DIAGNOSTIC_TEST	Echocardiography	Detection of signs of left ventricular hypertrophy, diastolic dysfunction, and valvular disease, which are common cardiac complications associated with Fabry disease, will be a key focus of the assessment. These abnormalities are indicative of the progressive cardiac involvement characteristic of the disease. Left ventricular hypertrophy reflects the thickening of the heart muscle, often caused by sphingolipid accumulation, while diastolic dysfunction highlights impaired relaxation and filling of the left ventricle. Valvular disease, including regurgitation or stenosis, further contributes to the cardiac burden in Fabry disease. Identifying and monitoring these conditions are essential for timely intervention and effective management of cardiac manifestations in affected patients.
DIAGNOSTIC_TEST	24 hour pulse wave analysis	Pulse wave analysis (PWA) is a non-invasive method used to assess the cardiovascular system. It uses a sensor to measure the pressure waves generated by the heart's contraction and the subsequent blood flow through the peripheral vessels. By analyzing these pressure waves, PWA can provide information about the elasticity of the arterial walls, the blood flow in the peripheral vessels, the blood pressure, and the arterial stiffness.
DIAGNOSTIC_TEST	24-hour blood pressure measurement	Blood pressure measurement to asses cardiovascular risk.
DIAGNOSTIC_TEST	1 hour ECG	One hour ECG to asses autonomic dysfunction in patients with Fabry disease.
DIAGNOSTIC_TEST	Ophthalmological consultation	Evaluation and monitoring of ocular manifestations of Fabry disease.
DIAGNOSTIC_TEST	Static retinal vessel analysis (SVA)	Comparable to DVA, SVA is a non-invasive and quick tool to examine the retinal microvasculature. SVA pictures will be analyzed using Vesselmap 2® (IMEDOS Systems GmbH, Jena, Germany). One eye will be examined, and three images will be taken with a focus on the optic disc at an angle of 50°. Roughly one disc diameter away from the optic disc, retinal veins and arterioles segments will be semi-automatically labeled. The Paar-Hubbard formula averages the central retinal arteriolar (CRAE) and central venular (CRVE) equivalents. The arteriolar-venular ratio will be calculated as CRAE/CRVE.

Timeline

• Start date: 2020-06-25
• Primary completion: 2021-09-01
• Completion: 2025-11-01
• First posted: 2025-01-06
• Last updated: 2025-01-06

Locations

1 site across 1 country: Germany