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dc.contributor.advisorDhaun, Neeraj
dc.contributor.advisorDear, James
dc.contributor.authorFarrah, Tariq Libaan Edward
dc.date.accessioned2022-10-17T14:56:53Z
dc.date.available2022-10-17T14:56:53Z
dc.date.issued2022-10-17
dc.identifier.urihttps://hdl.handle.net/1842/39434
dc.identifier.urihttp://dx.doi.org/10.7488/era/2684
dc.description.abstractCardiovascular disease (CVD) is the leading cause of long-term morbidity and mortality in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The mechanisms for this increased risk of CVD are poorly defined. Endothelin-1 (ET-1) is a potent vasoconstrictive, proinflammatory peptide that is regulated by the endothelium and immune system. AAV is defined by immune-mediated endothelial injury but there are few data examining endothelial dysfunction and the endothelin (ET) system as contributors to long-term CVD risk in these patients. In addition, there are no reliable, non-invasive methods to detect vascular injury in AAV. In this thesis, I explored endothelial function in patients with AAV, its relationship to the ET system, the potential cardioprotective effects of ET receptor antagonism and the role of retinal optical coherence tomography as a novel, non-invasive method of detecting acute and chronic vascular injury. I show that, compared to health, optimally-managed AAV patients in longterm remission have increased arterial stiffness, impaired endothelium-dependent vasodilatation and reduced endogenous fibrinolysis. These independent CVD risk factors independently associate with a higher plasma ET-1. Additionally, higher plasma ET-1 concentrations and worse fibrinolysis associate with fewer circulating monocytes and immunosuppression suggesting that treatments that affect monocytes may contribute to longterm CVD risk in AAV. These data also provide a novel therapeutic rationale for ET-receptor antagonism to reduce CVD risk in patients with AAV. I show that acute selective and dual ET-receptor blockade reduce arterial stiffness and blood pressure whilst increasing circulating measures of fibrinolysis in patient with AAV. These effects are in addition to standard therapy with renin-angiotensin-system blockade and may confer broad CVD protection in AAV patients. Using retinal optical coherence tomography (OCT) in patients with AAV, I show that the thinning of the choroid (a microvascular bed lying deep to the retina) associates with systemic vascular dysfunction. Furthermore, this thinning is more marked in patients with active AAV but improves following immunosuppressive treatment and disease remission. In summary, these studies demonstrate the contributions of the ET system to the pathophysiology of CVD risk in AAV. They also suggest that ET-receptor antagonism may be a novel therapeutic strategy to reduce CVD risk in AAV. Finally, retinal OCT may be a novel means of detecting and tracking vascular injury in patients with AAV. I show that acute selective and dual ET-receptor blockade reduce arterial stiffness and blood pressure whilst increasing circulating measures of fibrinolysis in patient with AAV. These effects are in addition to standard therapy with renin-angiotensin-system blockade and may confer broad CVD protection in AAV patients. Using retinal optical coherence tomography (OCT) in patients with AAV, I show that the thinning of the choroid (a microvascular bed lying deep to the retina) associates with systemic vascular dysfunction. Furthermore, this thinning is more marked in patients with active AAV but improves following immunosuppressive treatment and disease remission. In summary, these studies demonstrate the contributions of the ET system to the pathophysiology of CVD risk in AAV. They also suggest that ET-receptor antagonism may be a novel therapeutic strategy to reduce CVD risk in AAV. Finally, retinal OCT may be a novel means of detecting and tracking vascular injury in patients with AAV.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionRetinal fingerprints for precision profiling of cardiovascular risk Farrah TE, Webb DJ, Dhaun N. Nat Rev Cardiol. 2019 Jul;16(7):379-381en
dc.relation.hasversionAdvances in therapies and imaging for systemic vasculitis Farrah TE, Basu N, Dweck M, Calcagno C, Fayad ZA, Dhaun N. Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1520-1541en
dc.relation.hasversionThe eye, the kidney and cardiovascular disease: old concepts, better tools, new horizons Farrah TE, Dhillon B, Keane PA, Webb DJ, Dhaun N. Kidney Int. 2020 Aug;98(2):323-342en
dc.subjectCardiovascular diseaseen
dc.subjectendotheliumen
dc.subjectForearm venous occlusion plethysmographyen
dc.subjectEndothelin antagonismen
dc.subjectCirculating monocytesen
dc.subjectRetinal optical coherence tomographyen
dc.titleAssessment and modification of cardiovascular risk factors in ANCA-associated vasculitisen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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