Exercise testing and non-invasive haemodynamics in the assessment and monitoring of pulmonary hypertension: novel submaximal and peak exercise variables

Field: Medicine (Health Sciences)

Pulmonary hypertension is a disease characterised by progressive pulmonary
vascular remodelling and obliteration with consequent development of right
heart failure and ultimately death. First described many decades ago with a
median survival of less than 3 years and no available treatments, the
development of disease specific pulmonary vasodilator therapy has led to only
modest improvements in survival and it remains an almost universally fatal
disease.
One of the key symptoms of pulmonary hypertension is exercise intolerance,
primarily a consequence of the underlying right ventricular failure and an
inability to augment stroke volume on exercise. The gold standard diagnostic
test is right heart catheterisation but this is unattractive as a tool for ongoing
monitoring as it is invasive and not without risk, albeit that risk is small. As a
result most monitoring of disease progression and of treatment response is
carried out using surrogate markers, often exercise based such as the 6 minute
walk test.
Increasing attention is focused on the role of exercise both in that monitoring of
patients and also in helping to understand better the pathophysiology. The work
presented in this thesis therefore aimed to explore novel exercise derived
variables and noninvasive haemodynamic measurement as tools to improve our
understanding of the disease limitation, to enhance our monitoring of treatment
response and to give additional prognostic information.
In Chapter 3 the role of peripheral muscle oxygen extraction and exercise
limitation was explored by performing right heart catheterisation on exercise
with measurement of mixed venous oxygen saturation. This demonstrated that
patients with pulmonary hypertension demonstrate no evidence of impaired
oxygen extraction and that they appear to extract at least as much oxygen on
exercise as healthy individuals have been shown to in other studies. This
indicates that impairment of oxygen extraction is not a cause of exercise
limitation in pulmonary hypertension.
3
Chapter 4 describes a series of studies evaluating the potential role of the oxygen uptake efficiency slope in pulmonary hypertension. This variable derived from the oxygen consumption and ventilation across an incremental cardiopulmonary exercise test has demonstrated promise as a potential submaximal measure of exercise performance and predictor of survival in left heart failure. The studies conducted demonstrated that this variable is a measure of peak exercise performance in pulmonary hypertension, that it can be measure on submaximal levels of exercise and that it predicts survival in patients with Group 1 and Group 4 disease.
The studies described in Chapter 5 investigated the rates of recovery of heart rate and oxygen consumption after exercise and found that both could predict survival. In particular the rate of recovery of heart rate after exercise was demonstrated to be a strong predictor of survival on multivariate analysis, thus providing a further method of assessing prognosis with exercise.
Finally the ability of noninvasive measures of stroke volume to predict outcome was explored in the studies detailed in Chapter 6. The underlying haemodynamic abnormalities are not assessed when surrogate measures such as exercise testing are employed in patient follow up. Standard practice is to review patients 3 to 4 months after any change in treatment and to assess them using these surrogate measures. Acute haemodynamic changes are able to be detected invasively immediately after administration of pulmonary vasodilator therapy. This study therefore investigated the ability of two noninvasive methods of measuring stroke volume, inert gas rebreathing and cardiac MRI, to detect treatment response after only 2 weeks and assess how this related to functional improvement at the standard 4 months. The study found that haemodynamic changes were able to be detected at 2 weeks and these appeared to relate to changes in 6 minute walk distance at the same time point but did not appear to relate to 6 minute walk distance at 4 months. This study however did not reach its recruitment target and therefore further work is needed in this area.