Myocardial fibrosis and extracellular matrix remodelling in chronic heart failure : novel treatment and monitoring strategies.

Abstract

Myocardial fibrosis is a pathognomonic feature of CHF and cardiac collagen content has been shown to be an independent prognostic marker in patients with heart failure. Current pharmacological therapies in CHF utilising β-blockers and inhibitors of the renin-angiotensin-aldosterone axis have improved clinical outcomes and cardiac function, reduced cardiac size and partly abrogated myocardial fibrosis. However, despite their use at clinically effective doses cardiac remodelling continues, indicating that inhibition of pathological signalling pathways is incomplete, resulting in continued stimulation and production of pro fibrotic stimuli and ongoing myocardial fibrosis. Evaluation of myocardial fibrosis and extracellular matrix composition has traditionally been performed using myocardial biopsies. Non invasive assessment of myocardial collagen and the extracellular matrix has also been performed using peripheral venous blood markers. More recently novel cardiac MRI sequences have been shown to be useful for the purposes of cardiac tissue characterisation in heart disease, however their role in the reverse ventricular remodelling process of CHF is incompletely understood. The aim of this thesis was to explore the role of myocardial fibrosis and the extracellular matrix in CHF. A series of studies focused on three main components including; 1) the in vitro and in vivo evaluation of a novel pharmacological approach aimed at reducing myocardial fibrosis in post MI model of CHF, 2) the non invasive assessment of extracellular matrix turnover utilising blood markers in a clinical study of CHF and 3) the evaluation of a novel tissue characterisation cardiac MRI sequence in a clinical study of heart failure and in an large animal model of heart failure. Utilising in vitro studies, FT-011 a novel antifibrotic drug was initially shown to be effective at reducing collagen synthesis in cardiac fibroblasts at non toxic doses. FT-011 was subsequently evaluated in a rat post MI model of CHF. Its use was associated with improved ventricular function and a reduction of the cardiac collagen content of the non infarct zone of the left ventricle, without adversely affecting infarct zone healing. The reduction of pathological fibrosis was significantly correlated with beneficial cardiac remodelling and the magnitude of the beneficial effect was comparable to that of an ACE inhibitor. These results suggested that the anti fibrotic drug FT-011 may be potentially useful in the treatment of post MI CHF. CRT is a relatively new but well established treatment of CHF. Responders to CRT show evidence of ventricular reverse remodelling. The effect of CRT on myocardial fibrosis and ECM remodelling is incompletely understood. In this prospective study, patients undergoing CRT were evaluated at baseline and at six months following treatment to determine whether peripheral venous markers of collagen turnover and matricellular proteins change in association with reverse remodelling. The matricellular protein osteopontin, which has previously been shown to have a key role in myocardial fibrosis and ECM remodelling, was found to significantly reduce in responders to CRT but not in non responders or CHF control patients. These results suggested that the effect of CRT induced reverse remodelling is therefore at least partially due to beneficial remodelling of the ECM which can be monitored non invasively using venous biomarkers. In a further study, CHF patients were evaluated using a novel cardiac MRI T1 mapping sequence, which has been shown have usefulness in evaluating myocardial collagen content. Peripheral collagen markers and osteopontin were correlated with calculated T1 times. Osteopontin but not collagen markers were found to be significantly correlated with T1 times, further supporting the role of osteopontin in ECM remodelling and the role of T1 mapping in cardiac tissue characterisation. Finally, the ability of the cardiac MRI T1 mapping sequence to characterise cardiac tissue was evaluated utilising a sheep tachycardia cardiomyopathy heart failure model. Non contrast T1 mapping of explanted sheep hearts followed by a detailed histological evaluation of myocardial collagen content demonstrated for the first time a significant inverse relationship T1 times and cardiac fibrosis. These results confirmed that alteration in T1 times is at least in part due to a change in the myocardial collagen content and support the notion that non invasive tissue characterisation is a viable prospect.