Mechanisms of exercise intolerance in heart failure

Heart failure is a complex clinical syndrome where the heart is unable to maintain adequate cardiac output to meet the metabolic demands of tissues. This leads to a cascade of events that act to impair the oxygen transport system, giving rise to symptoms of fatigue and/or dyspnoea on exertion and, in more severe cases, at rest. Accordingly, exercise intolerance is a cardinal symptom of heart failure, and is a strong predictor of prognosis and mortality. As such, an individual's tolerance to exercise is inextricably linked to diagnosis in heart failure. The mechanisms for this exercise intolerance are still not fully understood and currently there is a debate surrounding whether exercise tolerance is governed primarily by impairments in cardiac function (i.e. oxygen delivery), or impairments at the skeletal muscle level (i.e. oxygen utilisation), or both. Resolving this issue has implications for improving and tailoring effective treatment in heart failure. The work presented in this thesis fulfils two major aims: (i) the development and validation of a computational model of circulatory and oxygen uptake dynamics, that is able to predict oxygen uptake measurements that are experimentally measured at the lungs, and at the skeletal muscle, for ramp incremental exercise and; (ii) the assessment of the clinical utility of using near infrared spectroscopy as a non-invasive tool to determine the locus of exercise intolerance in heart failure patients. The computational model of circulatory and oxygen uptake dynamics demonstrated that cardiopulmonary breath-by-breath gas exchange measurements alone are not sufficient to identify the locus of exercise intolerance in heart failure patients. However, with the addition of a model output that gives specific information on the skeletal muscle oxygenation dynamics, insights into the mechanisms governing exercise tolerance can be gained. Near infrared spectroscopy was utilised under two different experimental conditions. During ramp incremental exercise, it was shown that near infrared spectroscopy can provide specific information regarding the locus of exercise intolerance in heart failure, particularly, those with oxygen delivery limitations. In addition, using a novel technique to assess oxidative capacity, it was established that near infrared spectroscopy can be used to produce reliable assessment of skeletal muscle function and, thereby, proves a promising technique to identify those with skeletal muscle dysfunction.