346. Arterial stiffness, endothelial dysfunction &amp; impaired fibrinolysis: pathogenic mechanis of cardiovascular risk in ANCA-associated vasculitis
Creators: name: Farrah1, Tariq
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background</strong>: Cardiovascular disease is a leading cause of morbidity and mortality in anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). Mechanis are poorly understood, and risk-reduction strategies are lacking. AAV is defined by endothelial injury and immune system dysregulation. Endothelin-1 is an endogenous vasoconstrictor that contributes to endothelial function and is regulated by the immune system. The role of endothelin-1 in mediating cardiovascular risk in AAV is unknown. Thus, we assessed endothelial function, endogenous fibrinolysis, arterial stiffness and their relationships to the endothelin and innate immune syste <strong>Methods: </strong>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 The primary outcome for the case-control study was the difference in endothelium-dependent vasodilation between health and AAV. The primary outcome for the crossover study was the difference in pulse wave velocity (PWV) between treatment with placebo and selective endothelin-A antagonism. Parallel <em>in vitro</em> studies explored mechanism. <strong>Results: </strong><em>Case-control study:</em> 32 AAV patients in long-term remission and 32 matched controls were studied. Patients had a mean age of 5513 years, 23 (72%) were male, 17 (53%) were PR3+ and were a median time from diagnosis of 4 (1-13) years. Compared to health, AAV patients had ~30% reduced endothelium- dependent vasodilation (mean difference: -6.1 mL/100mL of tissue/min, p&lt;0.001) and ~50% reduced acute release of endothelial active tissue plasminogen activator (tPA, mean difference: 29 IU/100mL of tissue/min p&lt;0.001). AAV patients had increased arterial stiffness (PWV: 7.3±1.3 <em>vs.</em> 6.4±1.0 m/s, p=0.016). Plasma endothelin-1 was two-fold higher in AAV and independently predicted arterial stiffness and tPA release. <em>Crossover study:</em> 24 patients with AAV from the case-control study entered a randomised, double-blind, 3-phase crossover study. Compared to placebo, selective endothelin-A blockade reduced PWV (mean (95% CI) difference: 0.6 (0.4 to 0.8) m/s, <em>p</em>&lt;0.001) and increased tPA release in AAV patients. Similar effects were seen with dual endothelin-A/B blockade. <em>In vitro study:</em> Patients with AAV had increased platelet activation, more platelet-monocyte aggregates, and altered monocyte endothelin receptor function, leading to reduced endothelin-1 clearance. <strong>Conclusions:</strong> AAV patients in long-term disease remission have elevated cardiovascular risk, similar in magnitude to patients with previous myocardial infarction or advanced kidney disease. Endothelin-1 contributes, and our data support a role for endothelin-blockers to reduce this risk. <strong>Disclosures:</strong> None