Li, Kan Yan Chloe; (2024) Hierarchical, deep gene phenotyping of myocardial biopsies using synchrotron-based X-ray phase contrast imaging. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cardiomyopathies are a heterogeneous group of heart muscle disease (HMD) and represent a significant public health concern, with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) being among the most prevalent forms. These conditions are characterised by structural and functional changes in the heart, leading to impaired cardiac function and increased risk of sudden cardiac death (SCD). Accurate diagnosis and management of HMD rely heavily on myocardial biopsies, which can provide valuable insights into the underlying pathology. However, there is a lack of detailed analysis linking structural findings with genetic data. The first study introduces synchrotron-based cryo-X-ray phase contrast imaging (cryo-X-PCI) for imaging frozen myocardial biopsies, demonstrating its strengths in facilitating 3D morphological analysis and that DNA and RNA are not affected by cryo-X-PCI but rather by the sample preparation method used. However, no technique is perfect and recognising the limitations of cryo-X-PCI and that not all facilities have fresh frozen biopsies, the second study demonstrates the feasibility and safety of X-PCI for analysing formalin-fixed paraffin-embedded (FFPE) tissues, including myocardial biopsies from human COVID-19 victims. Building on these foundations, the third and fourth studies use multi-scale X-PCI to analyse myocardial biopsies and surgical resections from patients with various forms of cardiomyopathy. The third study focusses on HMD victims, including HCM, DCM and SCD, providing a detailed assessment of cardiomyocyte arrangement and microstructure, down to capillary level, while integrating relevant genetic testing information. The fourth study examines patients with hypertrophic obstructive cardiomyopathy and left ventricular outflow tract obstruction who underwent surgical myectomy, combining genetic data from whole exome sequencing to integrate structure with genetics. Overall, this thesis advances the field of myocardial biopsy analysis using X-PCI and demonstrates its potential for more accurate diagnosis of cardiomyopathies, highlighting the importance of integrating structural and genetic data for comprehensive understanding and management of these complex diseases.

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