Alfarih, Mashael; (2023) The deep phenotype of lamin A/C cardiomyopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Lamin A/C are structural proteins of the nucleoplasm known as intermediate filaments encoded by the LMNA) gene. The severity of cardiac disease in LMNA mutation carriers may range from subclinical to more severe forms culminating in advanced heart failure or sudden cardiac death, with many carriers requiring heart transplant or device implantation. Thus, early detection through family screening is essential to prevent serious consequences. There is a wide spectrum of phenotypic heterogeneity in lamin heart disease even in patients with identical mutations and the reasons for this are unknown. This heterogeneity is not limited to phenotype but also to disease course, and it is currently unclear why certain patients present with more brutal and rapid progressive course of disease than others. Through my PhD research I have sought to describe the deep imaging phenotype of lamin heart disease and to investigate its post-genomic myocardial phenotype. I have done this using cardiovascular magnetic resonance (CMR) and proteomics. With CMR, I unravelled the link between myocardial fibrosis and mechanics in LMNA gene mutation carriers compared to controls and other forms of dilated cardiomyopathy. To achieve this I quantified the volume and studied the patterns of focal fibrosis in lamin heart disease using the late gadolinium enhancement technique and I applied novel 4-dimensional morphological strain analysis approaches to look at deformation trajectories of the hearts across the cardiac cycle. In myocardial samples prospectively obtained from patients with end-stage lamin heart disease and ischaemic cardiomyopathy undergoing heart transplantation, I undertook discovery proteomics of whole heart atrial and ventricular myocardial tissue. In these patients I also undertook whole exome sequencing (WES) to gain a deeper understanding of the genetic architecture of participants in both lamin and control cohorts. To innovate within the field of CMR, I piloted the technical development of two novel complementary T1 mapping approaches: dark-blood saturation recovery with single-shot acquisition T1 mapping (SASHA) and dark-blood and systolic saturation-pulse prepared heart-rate independent inversion-recovery T1 mapping (SAPPHIRE), to understand their feasibility and their potential added value in the T1 mapping of thin-walled hearts.

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