VEGF-Antagonsim - eyesight and vascular function

Application for an Erwin-Schroedinger Fellowship - Abstract: Vascular endothelial growth factor antagonism eyesight and endothelial function Background. Vascular endothelial growth factor (VEGF) has been proposed to promote neovascular age-related macula degeneration (AMD), which is the leading cause for blindness in industrialized countries. Targeting VEGF-induced angiogenesis as therapeutic goal, intravitreal application of a VEGF-antagonist, ranibizumab or bevacizumab, has shown promising results in preventing vision loss in patients with neovascular AMD. Since VEGF has been linked to vascular integrity and endothelial function, VEGF-antagonism might contribute to endothelial dysfunction leading to an increase of cardiovascular risk. The goal of this research is to assess the impact of VEGF-antagonsim on endothelial function and surrogates of cardiovascular risk in patients with neovascular AMD. Specific aims. 1) To assess the change of endothelial function in patients with neovascular AMD receiving one VEGF-antagonist, either ranibizumab or bevacizumab, 2) to compare endothelial function between patients with neovascular AMD and patients with non-neovascular AMD, 3) to assess the impact of VEGF-antagonism by ranibizumab or bevacizumab on vascular compliance, vascular strain, circulating endothelial progenitor cells, inflammatory serum markers, serum levels of ranibizumab or bevacizumab, blood pressure and quality of life in patients with neovascular AMD in comparison with patients with non-neovascular AMD receiving no treatment. Methods. As primary outcome measure the change of endothelial function will be determined by flow-mediated dilation (FMD) of the brachial artery recorded by duplex ultrasound in patients with neovascular AMD receiving ranibizumab (N=30) or bevacizumab (N=30) at baseline and 8 weeks after initiation of treatment. Further, endothelial function will be compared with patients with non- neovascular AMD who will serve as controls (N=60). In all patients vascular strain (in the common carotid artery by duplex ultrasound and utilization of the respective software), vascular compliance (by carotid femoral pulse wave velocity), counts of circulating endothelial progenitor cells, levels of angiogenic and inflammatory serum markers, serum levels of ranibizumab/bevacizumab, blood pressure (24-hour monitoring) and quality of life (using SF-36 questionnaires) will be determined. Relevance. The scientific fellowship at the internationally renowned cardiovascular research center of the Clinic of Cardiology in Zurich offers the unique possibility for PD Dr. Oliver Schlager to study the impact of VEGF-antagonism on vascular function and associated cardiovascular risk. Thereby, the proposed project enables PD Dr. Oliver Schlager the acquisition of respective skills. After return to the Austrian research institution the integration of acquired skills in preexisting competences and knowledge will substantially support further research on vascular function and atherosclerosis.

The major aim of the study project was to assess whether and to what extent intraocular application of vascular endothelial growth factor (VEGF) antagonists affects systemic markers of vascular function in patients with neovascular, so-called wet, age-related macula degeneration (AMD). The main finding of this investigation was that systemic markers of vascular function were not affected upon intraocular application of VEGF antagonists in patients with wet AMD.AMD is the leading cause of blindness in the developed world. AMD can be classified as neovascular, so-called wet, AMD or non-neovascular, so-called dry AMD. Wet AMD is a chronic progressive disease, which is characterized by development of new blood vessels (neovascularization) and local leakage of fluid or blood. In patients with wet AMD current medical treatment comprises the local, intraocular application of VEGF antagonists. VEGF antagonists are injected intraocularly to prevent the underlying neovascularization. Currently, the two pharmacologically different VEGF antagonists, ranibizumab and bevacizumab, are available for intraocular injection in patients with wet AMD.Although the intraocular application of ranibizumab and bevacizumab constitutes a breakthrough in the management of patients with wet AMD, previous studies on the systemic use of the VEGF antagonists ranibizumab and bevacizumab raised concerns on cardiovascular safety of this promising treatment option. Therefore, the major goal of the present study was to assess flow-mediated dilation (FMD), which mirrors endothelial function and cardiovascular risk, and pulse wave velocity (PWV), as marker of vascular stiffness, in patients with wet AMD receiving either ranibizumab or bevacizumab. Further, 24-hour blood pressure was assessed in all included patients. Patients with dry AMD, who did neither receive ranibizumab nor bevacizumab, served as control group within this study.In total 88 patients were screened. Finally, 24 patients with wet AMD were randomly assigned to receive either ranibizumab or bevacizumab. Twenty-six patients with dry AMD served as control group. The inclusion of patients was stopped early because of three thrombo-embolic events, which occurred in patients with wet AMD who received VEGF antagonists.Comparing systemic parameters of vascular function between patients with wet AMD receiving VEGF antagonists and patients with dry AMD without VEGF antagonist treatment FMD, PWV and 24-hour blood pressure did not differ between both groups at inclusion and during follow up. Further, no within group changes of FMD, PWV and 24-hour blood pressure were observed through the follow up of patients with wet AMD.