Employing Gas Challenges and Breathing Manoeuvres to Assess Microvascular Functional Dynamics

Proper blood vessel function entails the transport of blood and modulation of perfusion in response to stimuli. This serves to maintain adequate blood pressure and nutrient delivery. The ability of blood vessels to modulate perfusion in response to demand is a key feature of microvascular integrity (MI). Loss of MI is a characteristic feature of endothelial dysfunction (ED) and is found in several conditions, including hypertension, chronic kidney disease (CKD) and diabetes. To date, most of the research on ED diagnosis has focused on the brain and although there is a clear link between cerebrovascular dysfunction and microvascular pathologies, little work has been done to diagnose extra-cranial ED. Assessment of MI necessitates two steps: a vasoactive stimulus to generate a response (i.e. vasoconstriction/ vasodilatation) and an imaging method to continuously monitor the response. The works presented in this thesis aim to further our understanding of microvascular reactivity with the aim of creating a non-invasive Magnetic Resonance Imaging (MRI) based technique to diagnose extra-cranial MD with the aid of a vasoactive gas challenge stimuli. To achieve this aim, we used a series of hypercapnic and hypoxic gas challenges to induce maximal hemodynamic responses so as navigate the spectrum of vessel calibre. We also employed a long life blood pool agent (Gadofosveset) to allow us to track the changes in vessel calibre. Using this agent, we could navigate the spectrum of vessel calibre in the high perfusion organs such as the kidney and low perfusion skeletal muscle. Furthermore, by employing a specific sequence of vasoactive gases we were able to assess the degree of ED in a hind limb ischemic rat model. Though still its infancy the works presented in this thesis offer us an introduction to the utility of using a gas challenge algorithm in conjunction with MRI to be used for the assessment of vessel health in a number of pathologies.Ph.D