Arterial stiffness, endothelial dysfunction and impaired fibrinolysis are pathogenic mechanisms contributing to cardiovascular risk in ANCA-associated vasculitis

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, p<0.001) and ~50% reduced acute release of endothelial active tissue plasminogen activator (tPA, mean difference: 29 IU/100mL of tissue/min p<0.001). AAV patients had increased arterial stiffness (PWV: 7.3±1.3 vs. 6.4±1.0 m/s, p=0.016). Plasma endothelin-1 was two-fold higher in AAV and independently predicted PWV and tPA release.
Crossover 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.