Shah, JS; (2016) Clinical characterisation of cardiac involvement in Anderson-Fabry Disease. Doctoral thesis , UCL (University College London).

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Text Shah_Clinical Characterisation of Cardiac Involvement in Anderson_submitted corrections 17-11-2016 combined.pdf.REDACTED.pdf Download (2MB) | Preview

Abstract

Background: Anderson – Fabry Disease (AFD) is an X-linked lysosomal storage disorder that results in a deficiency in lysosomal α-galactosidase A. This leads to an accumulation of glycosphingolipids in multiple cell types resulting in the characteristic angiokeratomata, acroparesthesiae, hypohidrosis, and corneal opacities of classical AFD. Although patients with AFD have a reduced life span, the pathogenesis and impact of cardiac involvement on prognosis remain unclear. The aim of this thesis was to clinically characterise cardiac involvement in AFD using a systematic cardiac assessment of a consecutive cohort of patients with AFD. / Methods: A cardiac assessment protocol including history and examination, 12 lead ECG, 24 hour ambulatory ECG monitoring, echocardiography and cardiopulmonary exercise testing were performed in a cohort of 122 consecutive patients. Subgroups had coronary flow reserve and evaluation of serum levels of MMP-9, TIMP-1 and TIMP-2 to assess coronary microvascular function and extracellular matrix (ECM) turnover, respectively. / Results: The main results of the thesis are as follows: (1) Tachy and brady arrhythmias are common and may contribute to premature death; (2) Left ventricular systolic impairment is common and decline in systolic function may represent a measure of disease severity; (3) objective evidence for exercise limitation is common and is related to overall disease severity as assessed with a validated disease severity score; (4) patients with AFD have markedly abnormal coronary microvascular function which does not improve with ERT; (5) patients with AFD have abnormal ECM turnover associated with overall disease severity. / Conclusion: Patients with AFD related cardiomyopathy have progressive disease characterised by heart failure and arrhythmia. It is likely that myocardial ischaemia and abnormal interstitial turnover are related in the pathogenesis of cardiac disease and complications. Patients with AFD need regular and continued cardiac follow up for early identification and treatment of cardiac complications.

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