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

被引:20
作者
Farrah, Tariq E. [1 ,2 ,3 ]
Melville, Vanessa [2 ]
Czopek, Alicja [1 ]
Fok, Henry [4 ]
Bruce, Lorraine [1 ]
Mills, Nicholas L. [1 ,5 ]
Bailey, Matthew A. [1 ]
Webb, David J. [1 ,2 ]
Dear, James W. [1 ]
Dhaun, Neeraj [1 ,2 ,3 ,6 ]
机构
[1] Univ Edinburgh, British Heart Fdn Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh, Scotland
[2] Univ Edinburgh, Western Gen Hosp, Clin Res Ctr, Edinburgh, Scotland
[3] Royal Infirm Edinburgh NHS Trust, Dept Renal Med, Edinburgh, Scotland
[4] St Thomas Hosp, Kings Coll London, Dept Clin Pharmacol, London, England
[5] Univ Edinburgh, Usher Inst, Edinburgh, Scotland
[6] Univ British Heart Fdn BHF, Queens Med Res Inst, Ctr Cardiovasc Sci, 47 Little France Crescent, Edinburgh, Scotland
基金
英国医学研究理事会;
关键词
ANCA vasculitis; cardiovascular risk; endothelin blockade; PLASMINOGEN ACTIVATOR RELEASE; A RECEPTOR ANTAGONISM; SYSTEMIC VASCULITIS; DEPENDENT VASODILATION; BLOOD-PRESSURE; ALL-CAUSE; IN-VIVO; INFLAMMATION; MONOCYTES; MORTALITY;
D O I
10.1016/j.kint.2022.07.026
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Cardiovascular disease is a complication of systemic inflammatory diseases including anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). The mechanisms of cardiovascular morbidity in AAV are poorly understood, and risk-reduction strategies are lacking. Therefore, in a series of double-blind, randomized case-control forearm plethysmography and crossover systemic interventional studies, we examined arterial stiffness and endothelial function in patients with AAV in long-term disease remission and in matched healthy volunteers (32 each 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 mechanisms. Compared to healthy volunteers, patients with AAV had 30% reduced endothelium-dependent vasodilation and 50% reduced acute release of endothelial active tissue plasminogen activator (tPA), both significant in the case-control study. Patients with AAV had significantly increased arterial stiffness (PWV: 7.3 versus 6.4 m/s). Plasma endothelin-1 was two-fold higher in AAV and independently predicted PWV and tPA release. Compared to placebo, both selective endothelin-A and dual endothelin-A/B receptor blockade reduced PWV and increased tPA release in AAV in the crossover study. Mechanistically, patients with AAV had increased platelet activation, more platelet-monocyte aggregates, and altered monocyte endothelin receptor function, reflecting reduced endothelin-1 clearance. Patients with AAV in long-term remission have elevated cardiovascular risk and endothelin-1 contributes to this. Thus, our data support a role for endothelin-blockers to reduce cardiovascular risk by reducing arterial stiffness and increasing circulating tPA activity.
引用
收藏
页码:1115 / 1126
页数:12
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