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Title: Imaging right ventricular function to predict outcome in patients treated for pulmonary hypertension
Author: Brewis, Melanie J.
ISNI:       0000 0004 6060 7285
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2017
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Pulmonary arterial hypertension (PAH) is a rare but devastating disorder of the pulmonary vasculature characterised pathologically by progressive intimal obliteration and vascular remodelling leading to increased pulmonary vascular resistance (PVR) and elevation in pulmonary arterial pressure (PAP), and clinically by functional impairment from breathlessness and ultimately death from right ventricular failure. Whilst the initial insult occurs in the pulmonary circulation, it is increasing recognised that survival relates to the ability of the right ventricle (RV) to adapt to this increased afterload. Despite a number of therapeutic advances in recent years, long-term survival remains poor, quality of life impaired by functional limitation and progression to RV failure often inevitable. In contrast, pulmonary hypertension (PH) related to chronic lung disease is relatively common, but is usually mild in severity with largely preserved RV function. The development of PH is however associated with greater functional impairment and worse survival and at present other than referral for lung transplantation there are no therapeutic options. Severe PH associated with lung disease is relatively rare, but shares many of the characteristics with PAH with more severe RV dysfunction and significant morbidity and mortality. It is also increasingly recognised in data from large PH registries, that increasing overlap exists between the two conditions, and what represents PAH with co-morbid lung disease (and therefore should receive specific PAH therapies) and what is PH secondary to lung disease (and therefore should not) increasingly muddied. What is clear is the critical role the RV plays in determining outcome in PH, but despite this studies on the impact of current therapies on RV function are few, and improvement or preservation of RV function is not an accepted clinical endpoint in pharmaceutical trials. Current methods of monitoring patient response to therapies are suboptimal, such as the established and commonly employed six minute walk distance (6MWD). The complex anatomy of the RV makes assessment of its function by modalities such as echocardiogram difficult. The development of simple, reproducible measures of RV function will both improve monitoring of PH patients but also facilitate acceptance of routine assessment of RV function in both clinical practice and pharmaceutical trials, and hopefully establish the optimal approach to RV dysfunction in PAH. Cardiac magnetic resonance imaging (CMR) is particularly suited to interrogating RV function, and has recently been established in the literature to provide prognostic significance in a number of disease states including PAH. At present, however, it is unclear what the optimal method of assessing RV function is, with a number of indices assessed by varying modalities associated with prognosis and therapeutic response in PAH. Recently research interest has developed in the potential utility of RV-arterial coupling in PH. From physiological principles, this metric of RV function has potential superiority over commonly employed indices such as RVEF or right atrial pressure (RAP) as it is less preload dependent. Its clinical use however is limited due to the need for instantaneous pressure-volume loops at varying levels of load in its derivation. It is however possible to estimate non-invasively by CMR. The aim of the work described by this thesis was to provide clarity on the optimal method of determining and monitoring RV dysfunction in PAH patients, and contrast this to patients with severe PH associated with lung disease treated with PAH therapies, where the aetiology of PH differs and utility of CMR to characterise RV function has not been explored. In chapter 3 PAH therapies given to severe PH/lung disease patients resulted in improvements in 6MWD (average ∆6MWD 24m, p=0.032), and NTproBNP (average ∆NTproBNP -396pg/mL, p=0.008), but to a lesser extent than IPAH patients. CMR imaging demonstrated that RV dysfunction (assessed by RV ejection fraction (RVEF), stroke volume (SV) and increased RV volumes) was prevalent, predicted prognosis in both conditions, and could be used to detect PH in lung disease by either measures of pulmonary vascular stiffness (relative area change of main pulmonary artery – RAC MPA) or RV mass (RVM). In Chapter 4, invasive pressure (Ees/Ea-P) and non-invasive volume (SV/ESV) estimates of RV-arterial coupling (determined by right heart catheterisation and CMR) were compared to other metrics of RV function in normal subjects, PAH and PH associated with lung disease patients as prognostic variables. Severe PH/lung disease patients displayed impaired RV adaptation in comparison to IPAH subjects, Ees/Ea-P 1.07 versus 1.37mmHg/mL, p=0.020. RV-arterial coupling estimated by the pressure method did not predict survival, but when estimated by the volume method (SV/ESV) did. Both RVEF and SV/ESV were independent predictors of outcome (HR 0.958, p=0.006 and HR 0.329, p=0.002 respectively). Invasive measures of RV function therefore provided no prognostic advantage over the more patient acceptable CMR. Finally in chapter 5, improvement in RV-arterial coupling assessed by CMR (SV/ESV) was seen after commencing PAH therapy (0.461 to 0.616, p=0.036). Survival was poorer in those with a fall in either RVEF or SV/ESV during therapy, with no superiority of either method of determining prognosis (Logrank p=0.002 for both). Change in RV function poorly related to change in 6MWD but closely related to change in NTproBNP. ∆NTproBNP but not ∆6MWD was an independent predictor of survival (HR 1.622 p=0.024 and HR 0.995 p=0.129 respectively) and therefore a useful monitoring tool of RV function and therapy response for the clinic. The results described in this thesis therefore suggest that RV function to predict outcome in patients with PH during treatment follow up is best determined by CMR imaging of RVEF or SV/ESV, with no clear benefit of re-evaluating invasive haemodynamics or pressure estimates of RV-arterial coupling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology ; R Medicine (General)