Non-invasive outcome measures in pulmonary hypertension

Lee, Wai-Ting Nicola (2013) Non-invasive outcome measures in pulmonary hypertension. MD thesis, University of Glasgow.

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Pulmonary hypertension (PH), a disease state affecting the pulmonary circulation, was first recognised in the 1950s. Obliteration of pulmonary capillary beds and vasoconstriction lead to elevated pulmonary vascular resistance (PVR) and increased right ventricular afterload. The direct consequence is impaired cardiac output (CO) response to exercise, resulting in progressive exercise limitation, and ultimately premature death from right heart failure. Despite the considerable expansion in pulmonary vasodilatory therapy in recent years, PH remains an incurable disease associated with high morbidity and mortality.
Exercise CO is an important outcome measure in PH as it is directly linked to the consequences of disease. Cardiac output is conventionally measured at right heart catheterisation (RHC). The invasive nature of this procedure does not permit serial measurements to be made readily during follow-up to assess disease progression or treatment response. As a result, six-minute walk distance (6MWD), a simple measure of submaximal exercise capacity, has been used as a surrogate of exercise CO and the primary end-point in most randomised controlled trials of pulmonary vasodilatory agents to date. However, there are recognised limitations to the ability of 6MWD to predict outcome, and this necessitates the development of alternative outcome measures which are non-invasive, reproducible and responsive to change. Measurement of CO using the inert gas rebreathing method (IGR) may be such an alternative to 6MWD. It is a direct measure of right heart function and hence disease-specific. It can be combined with submaximal constant-load exercise to provide an objective assessment independent of patient effort. This form of exercise would also allow isotime comparison of metabolic variables which were shown to be more sensitive than variables measured at peak exercise in demonstrating improved exercise capacity from therapeutic interventions in chronic obstructive pulmonary disease (COPD). Another potential alternative outcome measure is end-tidal carbon dioxide partial pressure (PETCO2). It is a marker of ventilatory inefficiency and was shown to correlate with disease severity in PH.
Accurate prognostication is central to PH management as it would inform treatment planning and patient counselling. Different strategies could be adopted to optimise the performance of existing prognostic factors. The predictive value of 6MWD may be improved by using % predicted 6MWD which adjusts for age, gender and anthropometric factors, and hence would give a more accurate representation of disease severity. A composite scoring system, combining key prognostic variables, would be more discriminatory than individual variables in predicting survival. Such prognostic equations have been derived from contemporary PH cohorts in France and the United States. Validation data published so far support their predictive value, but these equations may not perform as well in the United Kingdom (UK) as a locally derived risk score, due to differences in patient demographics and healthcare systems.
The aims of this thesis were to investigate the use of novel non-invasive exercise variables and prognostic algorithms as outcome measures in PH.
1. The first two studies evaluate the ability of IGR haemodynamic measurements and isotime metabolic variables during submaximal constant-load exercise, and PETCO2 during the six-minute walk test (6MWT) to predict treatment response.
2. The last two studies explore the prognostic value of % predicted 6MWD and a novel UK-based composite risk score.
The reproducibility and clinical correlates of IGR pulmonary blood flow (PBF) and stroke volume (SV) were determined. Changes in IGR PBF and SV and isotime metabolic variables, at rest and during submaximal constant-load exercise, were assessed after three months of new or modified disease-targeted therapy in patients with precapillary PH. IGR measurements were found to have good intersession reproducibility and correlate with conventional outcome measures including World Health Organisation functional class (WHO FC), 6MWD, N-terminal pro-brain natriuretic peptide (NT-proBNP) and Cambridge Pulmonary Hypertension Outcome Review (CAMHPOR) score. Resting and submaximal exercise IGR PBF and SV were able to detect treatment response, and may be more sensitive than 6MWD in detecting the effects of therapy in fitter patients. In comparison, isotime metabolic variables were less useful in detecting a treatment effect.
The metabolic response during the 6MWT was determined and changes in PETCO2 were assessed after 3 months of new or modified disease-targeted therapy. Therapy-induced changes in the nadir of PETCO2 (PETCO2 nadir) correlated with changes in 6MWD, but resting, end-of-walk or PETCO2 nadir did not improve significantly at follow-up. Post-hoc analysis demonstrated that the study was under-powered to detect a change in PETCO2 with therapy.
The prognostic performance of % predicted 6MWD, calculated using four different published reference equations, was compared with that of absolute 6MWD, at baseline and on treatment. Despite adjusting for physiological inter-subject variance, % predicted 6MWD is not superior to absolute 6MWD in predicting all-cause mortality. This may be related to limitations of existing reference equations or the use of all-cause rather than disease-specific mortality as the end-point.
Baseline mortality predictors were identified from a Scottish cohort of incident and treatment-naive PH patients, and used to derive a simple scoring system for survival prediction over time. When validated in an independent UK PH cohort, the Scottish Composite Score (SCS) was predictive of survival and able to provide further risk stratification in WHO FC III patients. It may perform better in UK populations than other published equations derived from PH cohorts in France and the United States.
In conclusion, IGR haemodynamic measurements may be useful as alternative outcome measures to 6MWD, and the SCS shows promise as the first UK-based composite risk score in PH. Further studies in larger cohorts are warranted to confirm their clinical utility.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Pulmonary hypertension, outcome, survival, exercise, cardiac output, stroke volume
Subjects: R Medicine > RZ Other systems of medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Supervisor's Name: Johnson, Dr. Martin Keith and Peacock, Prof. Andrew John
Date of Award: 2013
Depositing User: Dr Wai-Ting Nicola Lee
Unique ID: glathesis:2013-4296
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 May 2013 10:56
Last Modified: 30 May 2013 10:56

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