1. Arterial stiffness, endothelial dysfunction and impaired fibrinolysis are pathogenic mechanisms contributing to cardiovascular risk in ANCA-associated vasculitis
- Author
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Tariq E. Farrah, Vanessa Melville, Alicja Czopek, Henry Fok, Lorraine Bruce, Nicholas L. Mills, Matthew A. Bailey, David J. Webb, James W. Dear, and Neeraj Dhaun
- Subjects
Cross-Over Studies ,Endothelin-1 ,Receptors, Endothelin ,Fibrinolysis ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Pulse Wave Analysis ,Vascular Stiffness ,Cardiovascular Diseases ,Risk Factors ,Heart Disease Risk Factors ,Nephrology ,Tissue Plasminogen Activator ,Case-Control Studies ,Humans - Abstract
Cardiovascular disease is a complication of systemic inflammatory diseases and anti-neutrophil cytoplasm antibody-associated vasculitis (AAV) is an exemplar. Mechanisms are poorly understood, and risk-reduction strategies are lacking.In a series of double-blind, randomized case-control forearm plethysmography and crossover systemic interventional studies, we examined arterial stiffness and endothelial function in AAV patients in long-term disease remission and in matched healthy volunteers (n=32/group). The primary outcome for the case-control study was the difference in endothelium-dependent vasodilation between health and AAV, and for the crossover study was the difference in pulse wave velocity (PWV) between treatment with placebo and selective endothelin-A receptor antagonism. Parallel in vitro studies of circulating monocytes and platelets explored mechanism.Case-control study: Compared to healthy volunteers, AAV patients had ~30% reduced endothelium-dependent vasodilation (mean difference: -6.1 mL/100mL of tissue/min, pCrossover study: Compared to placebo, both selective endothelin-A and dual endothelin-A/B receptor blockade reduced PWV and increased tPA release in AAV. Mechanistically, patients with AAV had increased platelet activation, more platelet-monocyte aggregates, and altered monocyte endothelin receptor function, reflecting reduced endothelin-1 clearance. AAV patients in long-term remission have elevated cardiovascular risk. Endothelin-1 contributes, and our data support a role for endothelin-blockers to reduce this risk by reducing arterial stiffness and increasing circulating tPA activity.
- Published
- 2022
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