Myocardial fibrosis in heart failure

Abstract

Heart failure is a major contributor to mortality and morbidity, both in Australia and worldwide. Despite significant recent therapeutic advances, many patients ultimately progress to advanced cardiomyopathy. The subsequent burden of end-stage heart failure, with few eligible for cardiac transplantation, necessitates urgent research into the underlying pathophysiology of this important disease. Myocardial fibrosis has previously been identified as fundamental in the development of heart failure, as first described in ischaemic cardiomyopathy. Its importance in non-ischaemic cardiomyopathy has been more recently recognised, with considerable interest in possible therapeutic options to retard progression. In order to further elucidate the consequences of myocardial fibrosis and potential benefits of anti-fibrotic therapies, a non-invasive quantitative method for the analysis of myocardial fibrosis is highly desired. In Chapter 1 of this thesis, I provide an introduction and literature review encompassing the current knowledge of the pathogenesis of heart failure, and the pivotal role of myocardial fibrosis. Chapter 2 outlines the methodology of a novel non-invasive cardiac magnetic resonance (CMR) imaging technique, investigated in this thesis as a potential quantitative assessment of diffuse myocardial fibrosis. In Chapter 3 I report for the first time validation of this CMR imaging technique for the quantification of diffuse myocardial fibrosis. This study compares this prototype CMR sequence in patients with heart failure with control subjects. Additionally, histological confirmation and correlation with diastolic function is reported. Recognising the limitations of comparative histology using endomyocardial biopsy specimens, I then compared histological analysis in explanted hearts with in vivo CMR examination prior to cardiac transplantation. This whole heart analysis allowed not only validation of our novel CMR technique for diffuse myocardial fibrosis, but also for confirmation of an established CMR technique, late gadolinium enhancement (LGE), as representative of regional replacement myocardial fibrosis. Whilst this has been shown to correlate with fibrosis in areas of myocardial infarction, histological validation in non-ischaemic cardiomyopathy is lacking. To extend on my investigation into the consequences of myocardial fibrosis, I studied patients planned for implantation of an internal cardioverter-defibrillator (ICD) for the primary prevention of sudden cardiac death. All patients underwent CMR prior to device implantation, and were followed to monitor for a primary endpoint of appropriate device therapy, with a pre-specified composite secondary endpoint of all-cause mortality, appropriate ICD therapy or cardiac transplantation. Presence of LGE was significantly associated with likelihood of reaching both the primary and secondary endpoints. Finally, in Chapter 6, I report cross-sectional and longitudinal data in a group of patients with non-ischaemic cardiomyopathy. In this study, I present data independently correlating diffuse myocardial fibrosis quantified by CMR with symptoms of heart failure, and both regional and diffuse myocardial fibrosis independently predicting adverse outcomes. Publication of two of these papers has contributed to rapid proliferation of research into this important aspect of heart failure, with both papers highly cited. It is hoped that this doctoral work and ongoing post-doctoral studies will continue to advance our understanding of myocardial fibrosis in heart failure, ultimately with reduction in patient mortality and morbidity.