Arrhythmia In Fabry Disease

Roy, Ashwin ORCID: 0000-0003-4600-2733 (2025). Arrhythmia In Fabry Disease. University of Birmingham. Ph.D.

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Abstract

Fabry Disease (FD) is an X-linked lysosomal disorder, characterised by multi-organ accumulation of glycosphingolipid due to -galactosidase A deficiency. Cardiac Gb3 accumulation triggers left ventricular hypertrophy (LVH), interstitial fibrosis and chronic myocardial inflammation manifesting in the advanced stages; all of which are a trigger for therapy initiation. These form a powerful substrate for ventricular and atrial arrhythmia, responsible for the high burden of SCD and stroke. It is clear, however, that FD-cardiomyopathy develops before LVH is present. Yet it not well understood which abnormalities develop first, what the drivers are to these changes, and when these start. The aims of this thesis were to understand the pro-arrhythmic role of the atria in FD as a primary atrial myopathy, characterise early markers of FD cardiomyopathy that might provoke arrhythmia, identify novel risk predictors for arrhythmia and identify clinical strategies to document significant arrhythmia. This thesis has provided new insights into pro-arrhythmic, cellular, atrial alterations which are mimicked in-vivo. It has identified evidence of early cardiomyopathy in patients thought to be negative for a cardiac phenotype, diagnosed using routine investigations. This thesis also identifies potential mechanisms relating to ischaemia and inflammation that drive arrhythmia. Finally, it highlights the importance of risk stratification for arrhythmia and initiating continuous cardiac monitoring in those deemed high risk. The content of this thesis enhances our understand of some of the mechanisms driving this complex pro-arrhythmic inflammatory cardiomyopathy.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):