Novel Management of Heart Failure

Abstract

This thesis explores novel therapies in both acute decompensated heart failure and chronic heart failure. Heart failure (HF) continues to be a major medical problem worldwide. In this complex condition, haemodynamic and neurohormonal imbalances occur simultaneously. The presentation of HF is heterogeneous and prognosis, despite therapeutic advances remains poor. Opportunities to intervene arise in each stage of HF with unique targets according to the stage of disease. Despite proven therapies, including angiotensin converting enzyme inhibitors/ angiotensin receptor blockade, beta blockers and mineralocorticoid receptor antagonists, the five year mortality remains above 50% therefore the search for new and improved therapies remains necessary. Chapter 1: A literature review which discusses the epidemiology, pathophysiology and available treatments for HF and their limitations. In this literature review, an overview of the urocortin peptides is also provided. Urocortin-2, has potential as a therapeutic agent and is the key element involved in two studies discussed in this thesis. Chapter 2: Describes key methodologies incorporated in the three studies. Chapter 3: Reports the results of a study on the effects of urocortin-2 as an adjunct to conventional therapy in 53 patients hospitalised with acute decompensated HF. In this double-blind placebo-controlled randomised trial, urocortin-2 produced favourable haemodynamic effects in the acute decompensated setting without major adverse effects. Urocortin-2 warrants further investigation to explore its full potential on renal and hormonal effects as a therapeutic agent in acute decompensated heart failure. Chapter 4: Explores the effect of urocortin-2 on muscle sympathetic nerve activity (SNA) in eight healthy volunteers and four patients with stable HF. The results do not support the hypothesis that urocortin-2 inhibits muscle SNA in man as opposed to inhibition of cardiac SNA in conscious sheep. The response does not differ between healthy volunteers and HF patients. Chapter 5: Explores left atrial pressure and left atrial waveform effects of varying cardiac resynchronisation therapy (CRT) settings in eight patients with stable HF. Optimal CRT settings corresponded to lower left atrial pressure and more favourable waveform characteristics. The study demonstrated that it was feasible to use this implantable left atrial pressure sensor to guide CRT optimisation. Chapter 6: Summarises the key findings learned from the studies presented in Chapter 3-5. Areas of interests learned from these studies and proposed research direction are discussed. Chapter 7: References quoted in this thesis.