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By H. (Henning) Gall

Abstract

Pulmonary hypertension (PH) is a disease of the pulmonary vasculature with high morbidity and mortality in the affected individuals. We carried out research in two different populations: the Rotterdam Study, which is a population-based cohort study, and the Giessen PH registry, a patient population. In the present thesis we aimed to elucidate the prevalence of PH and its associated factors in the general population. We also studied improvement of prognostic and diagnostic evaluation in our patient population by means of biomarkers and exercise testing, and we analyzed the effects of combination therapy and personalized treatment approaches.\ud The participants of the Rotterdam Study had a mean age of 76.4 years. The prevalence of PH, measured by echocardiography, in this elderly Rotterdam population was 2.6%. We identified associated factors for PH in this population. Among the common diseases, COPD and left heart disease were associated with the highest prevalences of PH (chapter 2.1). Among parameters of left heart function and morphology, measures of diastolic function and left atrial diameter showed the strongest associations with pulmonary artery systolic pressure (PASP), measured by echocardiography (chapter 2.2). \ud The Giessen PH registry comprises the largest single center registry and is linked to a biobank. Wepresented baseline and survival data in chapter 3.1. Patients in our registry had similar baseline characteristics to those in other national registries in terms of age, six-minute walking test, New York Heart Association functional class, female-to-male-ratio, and hemodynamic parameters. Several prognostic markers were evaluated across all etiologic groups. \ud A definite diagnosis of PH requires invasive hemodynamic evaluation by means of right heart catheterization. This invasive evaluation carries risks and costs and is in some cases done for exclusion of the disease only. We aimed to find a diagnostic marker for PH to rule out or diagnose PH without invasive tests. In chapter 3.2, we found that the biomarkers soluble vascular endothelial growth factor receptor 1 and placental growth factor when analyzed together provide a relatively high diagnostic accuracy. This possibly enables us to obtain diagnostic information earlier in the long process from symptoms via screening to a definite diagnosis (chapter 3.2). \ud Previous work has shown pathophysiological links between PH and altered glucose metabolism (AGM). AGM and PH were linked to pathophysiological changes such as right heart congestion. Also, changes in signaling pathways, such as the bone morphogenic protein pathway, may play a role. We described the association of AGM with prognosis in patients with PH in chapter 3.3. Patients with PH who had an AGM as defined by an HbA1c above the median had a 3.9 times increased mortality as compared to those with an HbA1c below the median. \ud The concept of right ventricular contractile (RV) reserve is discussed in chapter 4.1. The increase in PASP upon physiological exercise is introduced as a possible measure of RV contractile reserve. An increase in PASP below the median was associated with an increased risk of mortality in a prospective cohort of patients with PH. \ud In chapter 4.2 we compared the acute vasoreactivity of patients with PH in response to inhaled nitric oxide and oral sildenafil. Both agents were shown to be of similar prognostic value. Nitric oxide is known to guide therapeutic decisions. We were able to show that sildenafil may also have the potential to personalize therapy. \ud Combination therapy of oral sildenafil with inhaled iloprost was evaluated in chapter 4.3. Sequential addition of a second drug on top of the first can improve functional class, pulmonary hemodynamics, and exercise capacity irrespective of the order in which these are given. Iloprost as a first therapy with later add-on of sildenafil shows the best long term survival in our retrospective uncontrolled study.\ud The main findings of this thesis are reviewed and discussed in detail in chapter 5, as well as relevant methodological issues

Topics: Pulmonary hypertension, prevalence, mortality, risk factors, combination therapy
Year: 2016
OAI identifier: oai:repub.eur.nl:79811

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