Therapeutic Implications of CMR Low Native T1 in Non-treated Non-hypertrophic Females With Fabry Disease (FD)

Condition(s) studied

Investigational drug(s) / intervention(s)

Decision tree for initiating treatment: 1. Cardiac Magnetic Resonance imaging to detect low native myocardial T1 2. National centralised expert committee to determine therapeutic indications 3. Recommendations forwarded to the local expert committee 4/ Local expert committee decision ( to start or not a specific therapy) 5/ Patiente decision

Study summary

Females with Fabry disease are characterized by variable phenotypes regarding time of onset, severity of symptoms and progression of disease due to the random inactivation of X chromosome leading to a cellular mosaic of mutated and wild genotypes.

Left ventricular hypertrophy (LVH) is a relatively late manifestation, appearing typically after the third decade in men and the fourth decade in women. Cardiac involvement progresses throughout life in Fabry females and is the first cause of death but in contrast to males, the loss of myocardial function and the development of fibrosis do not necessarily require myocardial hypertrophy in female with FD.

The presence of overt LVH and myocardial fibrosis has been shown to negatively affect treatment outcome, suggesting the importance of early initiation of treatment.

Multiparametric cardiac magnetic resonance (CMR) is able to detect sphingolipid infiltration by identifying a pre-LVH phase of cardiac FD defined by a low myocardial native T1, occurring in up to 60% of FD patients, with a concomitant slight elevated LV ejection fraction and electrocardiographic (ECG) changes. Low myocardial T1 values are independently associated with FD progression and are risk factors for clinical worsening.

Normal native T1 value is known to be higher in healthy young women than in men but prevalence of low native T1 in Fabry females has not been correctly assessed so far.

Treating Fabry females at the appropriate time is still a major issue and remains questionable as therapeutic and financial burden has to be balanced with severity status.

However, low native myocardial T1 in CMR is an early marker of cardiac impairment in FD that could justify adapting the therapeutic initiation notably in women. This is of paramount importance as early treatment may provide more benefit before occurrence of irreversible lesions such as LVH and fibrosis.

Eligibility

Primary outcome measure(s)

• Proportion of non-treated non-hypertrophic Fabry females for whom the indication for specific Fabry therapy (ERT or chaperone) is modified (i.e. established) based on additional information provided by low native myocardial T1 value. — Month 12
  A centralized expert committee will review all participant data and establish indication for specific Fabry therapy without then with CMR low native T1 value. First, indication for Fabry therapy will be established based on usual follow-up clinical and biological data. Then, CMR parameters will be displayed and change in indication for therapy will be collected.

Trial sites (12)

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