Eisenmenger syndrome physiology. mechanisms of disease, response to novel therapies and mortality risk stratification

Eisenmenger syndrome (ES) represents the extreme manifestation of pulmonary arterial hypertension in patients with congenital heart disease and is associated with significant morbidity and mortality. Yet, survival prospects and exercise performance vary significantly among ES patients. Those at higher risk of death may benefit from closer follow-up, more intense conservative management and may be considered for heart and lung or, occasionally, lung-only transplantation. Yet, mortality risk assessment is challenging and there were in 2013 no established mortality risk stratification methods. I explore in this thesis the pathophysiology of ES and the prognostic significance of commonly used clinical markers of disease progression. Chapters III – VI present analyses performed on a large cohort of patients with ES at the Royal Brompton Hospital in London while Chapter VII presents results of the largest multicentre study on mortality risk stratification in ES. Chapter III explores the exercise physiology and methods for assessment of exercise performance in ES. I demonstrate that six-minute walk test (6MWT) distance and arterial oxygen saturation (SO2) at rest significantly contribute to mortality risk stratification. Chapter IV and V discuss the role of inflammation and dysproteinaemia in ES and demonstrate that assessment of serum C-reactive protein and albumin levels may contribute to prognostication. Chapter VI discusses the challenges associated with multivariable mortality risk stratification in ES and the pathophysiologic rationale for collection of selected parameters in the multicentre study. Chapter VII presents the results of a multicentre study for assessment of mortality and predictors of death in contemporary ES patients. I demonstrate that five simple, non-invasive predictors of death, including age, SO2, type of shunt, 6MWT distance and presence or absence of pericardial effusion on echocardiography, enable accurate mortality risk stratification. These predictors identify a high-risk subgroup which may benefit from optimization of therapy or transplantation.