Assessment and modification of cardiovascular risk factors in ANCA-associated vasculitis

Cardiovascular 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

Pharmacological effects of raas blockade in ischemic nephropathy

Background: The management of ischemic nephropathy due to atherosclerotic renal artery stenosis has become increasingly conservative in the modern era, with current guidelines recommending optimized medical therapy as the initial step. The doubts raised by the recently published trials of revascularization strategies have led to a renewed focus on pharmacological strategies promoting blood pressure control and renal protection. It is essential to further elucidate the pathophysiological mechanisms underlying hypoperfusion induced renal microvascular dysfunction with subsequent tissue injury and fibrogenesis. The role of renin angiotensin aldosterone system as a mediator of the main pathophysiological consequences of ischemic nephropathy is well known. However, more recent experimental evidence on the adrenergic system and intrarenal tubular feedback mechanisms has stimulated new interest towards a multi-target therapeutic approach. Methods: This review focuses on the pharmacology of the principle therapeutic drug classes currently used in the treatment of atherosclerotic renal artery stenosis with an analysis of their metabolic aspects and use in clinical practice based on evidence from clinical trials. Results and Conclusions: An optimal pharmacologic approach is crucial for a successful prevention of renal injury and cardiovascular events in this high-risk population. Antihypertensive treatment should include renin angiotensin aldosterone system blockade medication not only for their antihypertensive properties, but especially for those cardio and renoprotectiv

The eye as a non-invasive window to the microcirculation in liver cirrhosis: a prospective pilot study

Microcirculatory dysfunction is associated with organ failure, poor response to vasoactive drugs and increased mortality in cirrhosis, but monitoring techniques are not established. We hypothesized that the chorioretinal structures of the eye could be visualized as a non-invasive proxy of the systemic microvasculature in cirrhosis and would correlate with renal dysfunction. Optical Coherence Tomography (OCT) was performed to image the retina in n = 55 cirrhosis patients being assessed for liver transplantation. OCT parameters were compared with established cohorts of age- and sex-matched healthy volunteers (HV) and patients with chronic kidney disease (CKD). Retinal thickness, macular volume and choroidal thickness were significantly reduced relative to HV and comparable to CKD patients (macular volume: HV vs. cirrhosis mean difference 0.44 mm3 (95% CI 0.26–0.61), p ≤ 0.0001). Reduced retinal thickness and macular volume correlated with renal dysfunction in cirrhosis (macular volume vs. MDRD-6 eGFR r = 0.40, p = 0.006). Retinal changes had resolved substantially 6 weeks following transplantation. There was an inverse association between choroidal thickness and circulating markers of endothelial dysfunction (endothelin-1 r = −0.49, p ≤ 0.001; von Willebrand factor r = −0.32, p ≤ 0.05). Retinal OCT may represent a non-invasive window to the microcirculation in cirrhosis and a dynamic measure of renal and endothelial dysfunction. Validation in different cirrhosis populations is now required