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PhD ceremony Mr. M.G. Dickinson: Pulmonary arterial hypertension. The role of increased blood flow and Egr-1

When:We 27-11-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. M.G. Dickinson

Dissertation: Pulmonary arterial hypertension. The role of increased blood flow and Egr-1

Promotor(s): prof. R.M.F. Berger

Faculty: Medical Sciences

Pulmonary Arterial Hypertension (PAH) is a leading cause of morbidity and mortality in patients with CHD. In these patients increased pulmonary blood flow (due to systemic-to-pulmonary shunting) is seen as an essential trigger for the formation of pulmonary neointimal lesions and thus PAH development. To date, neointimal lesions are regarded incurable, making PAH irreversible once these lesions occur. To develop new therapies, the molecular mechanism of this specific form of pulmonary vascular remodeling must therefore be unraveled.

The research identified gene expression profiles specifically related to the addition of increased pulmonary blood flow in experimental PAH. In this profile, 1 gene was of particular interest: Early Growth Response protein 1 (Egr-1). The spatiotemporal analysis of Egr-1 expression in this PAH model reveals that Egr-1 is up-regulated in the pulmonary arteries directly after induction of increased flow, but also later in the disease process. Specific oligonucleotides were used as a method to down-regulate vascular Egr-1 expression in the PAH model. In this study intravenous administration of catalytic oligodeoxynucleotides attenuated pulmonary vascular remodeling, including the development of occlusive neointimal lesions. Patients with PAH associated with CHD were studied, and pulmonary vascular Egr-1 expression was specifically increased in neointimal remodeling compared to medial hypertrophy remodeling in hypoxic PH and control vessels. Catheter related complications are described in 111 consecutive patients with pulmonary hypertension who were treated with long-term, continuous epoprostenol using a TIAP. TIAP complication rates in this study compare favorably with reported findings for tunneled catheter use (Hickman or Broviac).