Nordin, Sabrina Binti; (2019) The biology of myocardial Fabry Disease-insights from cardiovascular magnetic resonance. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Fabry disease (FD) is a rare, X-linked lysosomal storage disease leading to sphingolipid accumulation in multiple organs including the heart. Cardiovascular involvement is the leading cause of death with males affected earlier than females. Treatment is expensive and is less effective once overt cardiac involvement occurs. Ten years after the initial observation of a specific pattern of late gadolinium enhancement (LGE) in FD by our group, we observed that FD had reduced native myocardial T1 in the majority of patients with LVH and a smaller proportion in pre-hypertrophic FD. In this thesis, I have shown that early T1 lowering forms part of a detectable pre-hypertrophic phenotype in FD consisting of storage (low native T1), structural, functional and ECG changes. Continuing the development of new techniques for FD using T2 as a marker of oedema and blood biomarkers, I have shown that LGE in FD may be inflammation. By assembling the largest ever FD CMR cohort, with single timepoint imaging (during my thesis), I present data that is most consistent with myocyte storage starting in childhood, accumulating faster in males with two, partially independent processes: a gender independent scar/inflammation regional response (LGE) and, in males, apparent triggered myocyte hypertrophy. Combining these insights, I proposed different phases of cardiac involvement by CMR: an accumulation phase; an inflammation and myocyte hypertrophy phase; and later a fibrosis and impairment phase. Finally, I serially evaluated the changes observed in cardiac phenotype, myocardial storage and inflammation in relation to treatment with enzyme replacement therapy after one year. In conclusion, using an exemplar, “clean” rare monogenic disease, FD, at scale and by applying new techniques I have created a richer, more complex disease model of myocardial phenotype development with new insights and new potential therapeutic targets for FD, but also with potential insights into other diseases.

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