Characterisation of Heart Involvement in Fabry Disease With T1 Mapping (T1)

October 19, 2021 updated by: Manchester University NHS Foundation Trust

Fabry disease is a rare lysosomal storage disorder characterised by a genetic deficiency in the α-galactosidase enzyme. This deficiency leads to a progressive accumulation of a fatty substance, called glycosphingolipids within a specific part of our cells called the lysosome. This lysosomal accumulation can have devastating effects on patients with Fabry disease, affecting multiple organs. Heart involvement is particularly feared because it is the leading cause of death in Fabry disease.

Cardiovascular magnetic resonance imaging (cardiac MRI) is a relatively new heart imaging technique. A cardiac MRI technique called T1 mapping can measure the magnetic relaxation properties of heart tissue. T1 mapping is important in Fabry disease because glycosphingolipids have distinct magnetic relaxation properties. The abnormal build up of glycosphingolipid within the heart may be detectable using T1 mapping. This accumulation of glycosphingolipid could identify an earlier form of Fabry disease. Moreover, it is postulated that T1 mapping may inform prognosis and response to therapy.

Whilst promising, further investigation and development of this innovative technique in Fabry disease is required. This study aims to find out more about T1 mapping in Fabry disease. Patients referred for clinical cardiac MRI scanning will also undergo T1 mapping. T1 mapping results will be correlated with other markers of disease severity. This will allow heart muscle T1 to be determined in a larger population of Fabry patients than currently exists in the literature and T1 to be characterised across a wider range of Fabry disease severity than currently exists in the literature.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Anderson-Fabry disease (Fabry disease) is a genetic lysosomal storage disorder. Lysosomes are structures found within cells that contain enzymes which break down waste products and foreign material. In Fabry disease there is an inborn deficiency of an enzyme called α-galactosidase A. This leads to progressive accumulation of a fatty substance, called glycosphingolipid, in the lysosomes.

Accumulation of glycosphingolipid in cells can affect the function of many organs, but in particular it affects the heart, the brain and nerves and the kidneys. It manifests as severe and chronic limb pain, progressive kidney dysfunction, transient ischaemic attacks and strokes, coronary artery disease and heart failure. Heart involvement is particularly important because it is responsible for the majority of deaths in patients with Fabry disease.

Fabry disease affects between 1:17,000 to 1:117,000 people, although the prevalence is likely to be underestimated due to difficulties in diagnosis. It is seen across all ethnic and racial groups. It is a chronic disease with significantly reduced survival (median age of death 50). The culprit gene is carried on the X chromosome, therefore males are generally more severely affected than females, with symptoms beginning in childhood or adolescence. Manifestations are more variable in females, from no apparent disease to full expression, but up to 90% have symptoms.

There is no cure for Fabry disease, however enzyme replacement therapy (ERT), which consists of providing affected patients with the deficient enzyme, is available. ERT has been demonstrated to reverse or slow disease progression before irreversible end-organ damage has occurred. However, there are no uniform guidelines as to which patients should receive ERT, when to start it, how to monitor response and when to stop it. As such, patient care is far from optimal, with patients who would benefit from ERT often getting it too late or potentially not getting it at all. Furthermore, ERT is being started in patients in whom the disease is irreversible, or continued in patients in whom it is no longer of benefit. As well as the implications for patient care, this has significant implications for healthcare provision, given that ERT costs in excess of £100,000 per patient per year.

The reason why there are no good guidelines for ERT is that there is no good test to determine organ involvement or organ response to therapy. As explained above, heart involvement is particularly important but the current technique to assess heart involvement (ultrasound scanning of the heart (echocardiography)) is insensitive to accumulation of glycosphingolipid. Echocardiography allows assessment for heart muscle thickening and impairment of gross pumping function, but such changes occur late and are insensitive for assessing response to ERT. Heart muscle biopsy can determine glycosphingolipid accumulation, however this is very invasive, expensive and not an acceptable technique for this purpose.

A non-invasive technique to detect early heart involvement in Fabry disease, that would guide initiation of ERT, monitor response to ERT and determine which patients will not benefit from ERT, is urgently required, both in terms of improving and individualizing patient care and in terms of optimizing healthcare provision.

Cardiovascular magnetic resonance imaging (cardiac MRI) is a relatively new clinical heart imaging technique. It provides detailed and often unique information about heart structure and function. Cardiac MRI images are acquired using magnetic fields. It is free from ionizing radiation; indeed it is considered to be "one of the safest medical procedures currently available" (www.nhs.uk), and thus is an ideal technique for disease surveillance and treatment monitoring.

One of the unique attributes of cardiac MRI is its ability to non-invasively characterise the make-up of heart muscle tissue. Just like all tissues have mass, all tissues have magnetic properties. A cardiac MRI technique called T1 mapping can measure the magnetic relaxation properties of tissues. T1 mapping techniques have been used to assess other organs for many years, but have only relatively recently been applied to the heart.

Fat has different magnetic properties to heart muscle; specifically it has faster magnetic relaxation than heart muscle. This difference can be measured using T1 mapping - fat has a shorter (or lower value) T1 relaxation time than heart muscle.

As described above, in Fabry disease, there is accumulation of glycosphingolipid in the heart. Also as described, glycosphingolipid is a fatty substance. Therefore, accumulation of this fat in the heart could theoretically be detected using the T1 mapping technique.

Two small studies have demonstrated low T1 mapping values in Fabry disease patients in comparison to healthy volunteers and in comparison to patients with other heart conditions that cause heart muscle thickening (Sado et al Circ Cardiovasc Imaging. 2013;6:392-398 and Thompson et al Circ Cardiovasc Imaging. 2013;6:637-645). Interestingly, low T1 mapping values were seen in the absence of any other detectable changes in heart structure and function, suggesting that this technique could allow early detection of heart involvement in Fabry disease. T1 mapping and other allied cardiac MRI techniques (late gadolinium enhancement and extracellular volume quantification) have also been used to demonstrate heart muscle scarring in Fabry disease, which is irreversible and thus unlikely to be amenable to ERT.

Potentially therefore, cardiac MRI T1 mapping could allow early detection of heart involvement in Fabry disease and thus better guide initiation of ERT, allow monitoring of heart response to ERT and, together with the allied cardiac MRI techniques described, determine when advanced disease is present and thus when ERT should be stopped or is not appropriate to initiate.

Whilst promising, further investigation and development of this innovative technique in Fabry disease is required. This study aims to find out more about T1 mapping in Fabry disease. Patients referred for clinical cardiac MRI scanning will also undergo T1 mapping. T1 mapping results will be correlated with other markers of disease severity. This will allow:

  1. Heart muscle T1 to be determined in a larger population of Fabry patients than currently exists in the literature
  2. T1 to be characterised across a wider range of Fabry disease severity than currently exists in the literature.

Study Type

Observational

Enrollment (Actual)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Manchester, United Kingdom, M239LT
        • Manchester Univiersty Foundation Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with Fabry disease who are undergoing cardiac MRI scanning as part of their usual clinical care.

Description

Inclusion Criteria:

Patients with Fabry disease Patients attending for a clinical cardiac MRI scan

Exclusion Criteria:

Patients who have a contraindication to cardiac MRI scanning (including pacemakers, defibrillators, intra-ocular metal, prohibitive intracranial aneurysm clips, severe claustrophobia, inability to lie flat).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Myocardial T1 relaxation time
Time Frame: through study completion, an average of 3 years
T1 time derived from myocardial T1 mapping
through study completion, an average of 3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Left ventricular ejection fraction
Time Frame: through study completion, an average of 3 years
Derived from left ventricular volumetric cine imaging
through study completion, an average of 3 years
Left ventricular mass
Time Frame: through study completion, an average of 3 years
Derived from left ventricular volumetric cine imaging
through study completion, an average of 3 years
Right ventricular ejection fraction
Time Frame: through study completion, an average of 3 years
Derived from right ventricular volumetric cine imaging
through study completion, an average of 3 years
Myocardial T2 relaxation time
Time Frame: through study completion, an average of 3 years
T2 time derived from myocardial T2 mapping
through study completion, an average of 3 years
Adverse events
Time Frame: Retrospective - data collection to be finalised by the end of February 2021
Exploratory composite end-point of adverse events during follow-up
Retrospective - data collection to be finalised by the end of February 2021

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 12, 2014

Primary Completion (Actual)

December 31, 2020

Study Completion (Actual)

December 31, 2020

Study Registration Dates

First Submitted

January 11, 2021

First Submitted That Met QC Criteria

January 12, 2021

First Posted (Actual)

January 13, 2021

Study Record Updates

Last Update Posted (Actual)

October 20, 2021

Last Update Submitted That Met QC Criteria

October 19, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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