Modification of cardiovascular risk factors in anti-neutrophil cytoplasm antibody-associated vasculitis

Abstract

Anti-neutrophil cytoplasm antibody-associated vasculitis (AAV) is an autoimmune disease characterised by damage to the vascular endothelium lining small blood vessels. It can affect any organ in the body. Cardiovascular disease (CVD) is the leading cause of mortality for patients with AAV. The mechanisms for this are poorly understood although are thought to include damage to the vascular endothelium. Among its many functions, the endothelium produces endothelin-1 (ET-1) a potent vasoconstrictor that acts via endothelin receptor subtype A (ETA) receptors. It also regulates fibrinolysis through production of tissue plasminogen activator (tPA). AAV leads to endothelial dysfunction characterised by an ET-1 mediated increase in vascular tone and a reduction in tPA. Importantly, both of these markers, as well as the linked state of arterial stiffness are independent predictors of CVD.

Patients with AAV in long-term disease remission with risk factors for CVD controlled have reduced endothelium-dependent vasodilatation, reduced tPA and increased arterial stiffness compared to matched healthy controls. A short-term infusion of an ETA receptor blocker improves stimulated tPA release and arterial stiffness. Currently there is limited guidance for clinicians on reducing the risk of CVD for patients with AAV. Many patients are prescribed a blocker of the renin-angiotensin-aldosterone system which reduces risk of CVD by reducing activity of the angiotensin II type 1 (AT1) receptor. In this thesis I investigate whether the improvement in endothelial function seen with a short-term infusion of an ETA receptor blocker can be maintained longer-term in patients with AAV and whether the addition of an ETA receptor blocker improves endothelial function in addition to an AT1 receptor blocker. In an exploratory study I also investigate the potential for using optical coherence tomography (OCT) to monitor changes in the choroid and retina in response to ETA and AT1 receptor blockade. Thinning of the choroid has been shown to occur with progressive kidney disease or proteinuria and these changes are reversible after a kidney transplant, a treatment associated with an improvement in renal function and known to improve cardiovascular outcomes. If changes in the choroid can be shown to reliably change in response to therapies proven to modify cardiovascular risk then OCT scanning could potentially represent a novel, non-invasive method of monitoring a patient’s response to treatment or prognosticating their future cardiovascular risk.

Thirty-two patients with AAV completed a randomised, double-blind, active-control, parallel group study. Patients were randomised 1:1 to treatment with sparsentan, a first-in-class dual ETA and AT1 receptor blocker or irbesartan, an AT1 receptor blocker to represent current treatment. Using the gold standard test of a forearm blood flow study I show that six weeks of treatment with a dual ETA and AT1 receptor blocker significantly improves endothelium-dependent vasodilatation and increases stimulated release of tPA whereas AT1 receptor alone does not improve either measure of endothelial function. I also show that dual ETA and AT1 receptor blockade is non-inferior to AT1 receptor blockade alone in improving other markers of future cardiovascular risk including reducing blood pressure, arterial stiffness and proteinuria. I demonstrate that dual ETA and AT1 receptor blockade causes a significant increase in choroidal thickness and macular volume whereas AT1 receptor blockade alone does not change either measure.

In summary, these studies demonstrate that dual ETA and AT1 receptor blockade significantly improves endothelial function in patients with AAV in long-term disease remission whereas AT1 receptor blockade alone does not. Dual receptor blockade is non-inferior at improving a range of other markers of future cardiovascular risk. These findings have important implications for patients with AAV as they suggest that addition of ETA receptor blockade to currently available therapies would reduce long-term cardiovascular risk. Furthermore, these findings suggest that further studies are indicated in other pathologies known to be associated with endothelial dysfunction as addition of ETA receptor blockade may have a similar positive effect on endothelial function. I also show that improving endothelial function with a systemically acting drug induces changes detectable with an OCT scanner, supporting the idea that OCT scanners could be used to monitor response to treatment for systemic diseases.