Mechanisms and Management of Breathlessness in Chronic Heart Failure

Background: The pathophysiology of dyspnoea (‘breathlessness’) is poorly understood and treatment options limited. This is particularly true for heart failure in which dyspnoea is a cardinal symptom, even when the heart failure is optimally managed. This thesis aims to untangle mechanisms and utilise this knowledge to optimise heart failure management. It focuses on the potential of nebulised furosemide as an adjunct treatment, given its excellent safety record and existing evidence that it modulates dyspnoea via direct action on lungs. Methods: A multi-dimensional questionnaire was used to survey the prevalence of dyspnoea in the heart failure community. A randomised, double blind, placebo-controlled crossover trial (RCT) was then performed in healthy participants to determine the specific components of dyspnoea that are relieved by the action of furosemide on the lungs. This study led to the design of a feasibility RCT in patients with heart failure using the visual analogue scale (VAS) ratings of the ‘air hunger’ (AH) component of dyspnoea as the primary outcome measure. The RCT itself; i) addressed other issues that could account for variability in relief seen in previous studies, ii) explored blood biomarkers of heart failure in relation to dyspnoea and iii) provided guidance for future definitive clinical trials. Results: 1) 47% of patients experienced dyspnoea in the community. Dyspnoea-12 scores correlated with New York Heart Association class, with many in class III experiencing dyspnoea at rest. 2) Nebulised furosemide specifically relieved AH induced in healthy participants but did not affect the 'work/effort' component. Relief was only with nebulised, not intravenous furosemide. 3) Breathing furosemide quickly or slowly did not alter dyspnoea relief, but ventilation was not matched. 4) Cardiopulmonary exercise testing (CPET) produced an average VO2peak of 54±15% predicted, with a measurable anaerobic threshold in 73% of tests and raised dyspnoea to 42±19%VAS. 5) Nebulised furosemide resulted in no significant improvements in exercise capacity. 6) Cardiac biomarkers increased appropriately and returned to baseline within 1 hour of exercise. The maximal absorption efficiency of nebulised furosemide was 2%. Conclusion: 1) Dyspnoea is a prevalent symptom in heart failure, comparable to chronic obstructive pulmonary disease. The NYHA classification may require clarification regarding presence of breathlessness at rest. 2) Relief of dyspnoea with nebulised furosemide occurs via a mechanism within the lungs and should be targeted at those in whom ‘air hunger’ predominates. 3) CPET is a feasible method for dyspnoea assessment in heart failure. 4) Fully powered RCT of nebulised furosemide in heart failure are warranted taking on board the preliminary information gathered in this thesis to optimise treatment effect