Investigating the impact of non-alcoholic fatty liver disease on the pathogenesis and progression of heart failure with preserved ejection fraction

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Leggat, Jennifer 

Heart failure with preserved ejection fraction (HFpEF) is a growing public health concern due to its increasing incidence alongside a lack of effective therapeutics. Understanding how this condition develops is therefore of the utmost importance in order to develop preventative strategies. As such, investigation of the cardiac functional effects of HFpEF risk factors is crucial; one such risk factor is non-alcoholic fatty liver disease (NAFLD). NAFLD has been shown to both predispose individuals to HFpEF and to increase HFpEF severity, independently of cardiovascular risk factors. However, whether the coexistence of these conditions is mediated independently by comorbid metabolic dysregulation, or whether the steatotic liver itself can exert direct cardiotoxic effects, is as yet unknown. Accordingly, the aims of this thesis are to establish whether hepatic steatosis in itself is sufficient to detrimentally impact myocardial diastolic function, and to investigate mechanisms by which this might occur. In Chapter 3, the association between NAFLD and HFpEF is established in a murine model, demonstrating that murine models are suitable for use in this research. In Chapter 4, appropriate models of specific hepatic steatosis and diastolic dysfunction are developed for use in Chapter 5, in which we demonstrate that hepatic steatosis is sufficient to exacerbate both surgically- and chemically-induced diastolic dysfunction. Potential mechanisms underlying this association are investigated in Chapter 6, in which we demonstrate that factors secreted by fatty hepatocytes are capable of altering cardiomyocyte physiology. We further identify that diastolic dysfunction in NAFLD is associated with increased myocardial lipogenic lipid content, and demonstrate that altering myocardial lipid composition is sufficient to alter cardiomyocyte morphology and function. In Chapter 7, we demonstrate that reducing hepatic de novo lipogenesis attenuates diastolic dysfunction, in association with reduced serum lipids and reduced myocardial lipogenic lipid content, suggesting that hepatic steatosis may drive dyslipidaemia which may alter myocardial lipid handling, resulting in diastolic dysfunction. Together, these data demonstrate that hepatic steatosis can directly contribute to the pathogenesis of cardiac dysfunction, and allude to dyslipidaemia and cardiac lipid mishandling as potential mediators of liver-heart cross-talk in the context of NAFLD and HFpEF. Following further study to fully characterise this mechanism, this work could therefore facilitate the future development of targeted therapies against dyslipidaemia to prevent the pathogenesis of HFpEF in NAFLD patients.

Vidal Puig, Antonio
Krieg, Thomas
heart failure, non-alcoholic fatty liver disease, heart failure with preserved ejection fraction, lipotoxicity, diastolic dysfunction, lipid metabolism, metabolic syndrome
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
British Heart Foundation, National University Hospital of Singapore