Patel, Vimal; (2018) Myocardial fibrosis in hypertrophic cardiomyopathy. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Hypertrophic cardiomyopathy (HCM) is characterised by myocardial hypertrophy, fibrosis and abnormal vascular pathology and is usually caused by mutations in sarcomeric protein genes. Histological studies and in vivo imaging with cardiac magnetic resonance imaging (CMRI) have shown that myocardial fibrosis is an important entity that contributes to disease progression. However, little is known about the regulation of genes involved in collagen synthesis and metabolism, the pathways that contribute to the development of myocardial fibrosis and whether this is an early pathological process which ultimately leads to the development of the overt phenotype in genetic mutation carriers. Furthermore, the contribution of fibrosis on myocardial function has been poorly defined. In this thesis, I identified that myocardial genetic expression of collagen is upregulated in patients with HCM and this is paralleled by elevated levels of procollagen in plasma. The genetic expression of transforming growth factor beta (TGF-β) and its downstream mediator connective tissue growth factor was also enhanced in HCM and correlated with collagen I and III RNA levels, suggesting a central role of TGF-β in mediating fibrosis. Plasma markers of collagen synthesis and metabolism were also increased in sarcomeric mutation carriers without hypertrophy, suggesting that fibrosis may be an early process that contributes to the development of the overt phenotype. Plasma levels of procollagen I were higher in patients with non-sustained ventricular tachycardia and focal fibrosis identified by CMRI was associated with impaired systolic deformation. Diffuse fibrosis beyond that seen in healthy controls also correlated with a reduction in systolic function. Together, the findings of this thesis support the hypothesis that myocardial fibrosis is an active process in HCM that precedes clinical phenotype. Myocardial fibrosis is at least in part mediated by the TGF- β pathway and associated with impaired systolic performance and may contribute to arrhythmic risk in HCM.

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