Evaluating the microcirculation in early phase clinical trials: novel methodologies and interventions

Abstract

The endothelium is a crucial component of the vascular system, and its proper function is vital for microcirculatory function and by extension cardiovascular health. Hence, endothelial dysfunction is involved in a majority of cardiovascular disease and poses a high societal burden. Endothelial nitric oxide bioavailability is essential for a healthy microcirculation. The first half of this thesis investigates the reliability of imaging techniques that non-invasively assess the microcirculation and nitric oxide bioavailability, including laser speckle contrast imaging, Doppler flowmetry, dark field microscopy, skin fluorescence imaging and near infrared spectroscopy. In addition, the vascular effects of a mixed meal and a far-infrared light emitting patch, as measured with the imaging methods, are assessed. Finally, differences in microcirculatory function in people with mitochondrial disorders and healthy volunteers are explored. In the second half of the thesis, first-in-human and proof-of-mechanism studies with a soluble guanylyl cyclase stimulator and a phosphodiesterase inhibitor are described, drugs thought to enact some of their effects through modulation of vascular function downstream of nitric oxide. The thesis concludes with a critical appraisal of the investigated imaging modalities and their potential for inclusion in future clinical trials with drugs aiming to affect the microcirculation.