PMID- 35998848
OWN - NLM
STAT- MEDLINE
DCOM- 20221025
LR  - 20240320
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Linking)
VI  - 102
IP  - 5
DP  - 2022 Nov
TI  - Arterial stiffness, endothelial dysfunction and impaired fibrinolysis are 
      pathogenic mechanisms contributing to cardiovascular risk in ANCA-associated 
      vasculitis.
PG  - 1115-1126
LID - S0085-2538(22)00633-0 [pii]
LID - 10.1016/j.kint.2022.07.026 [doi]
AB  - 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.
CI  - Copyright (c) 2022 International Society of Nephrology. Published by Elsevier Inc. 
      All rights reserved.
FAU - Farrah, Tariq E
AU  - Farrah TE
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK; Clinical Research 
      Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK; 
      Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
FAU - Melville, Vanessa
AU  - Melville V
AD  - Clinical Research Centre, University of Edinburgh, Western General Hospital, 
      Edinburgh, UK.
FAU - Czopek, Alicja
AU  - Czopek A
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK.
FAU - Fok, Henry
AU  - Fok H
AD  - Department of Clinical Pharmacology, Kings College London, St Thomas' Hospital, 
      London, UK.
FAU - Bruce, Lorraine
AU  - Bruce L
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK.
FAU - Mills, Nicholas L
AU  - Mills NL
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK; Usher Institute, 
      University of Edinburgh, Edinburgh, UK.
FAU - Bailey, Matthew A
AU  - Bailey MA
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK.
FAU - Webb, David J
AU  - Webb DJ
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK; Clinical Research 
      Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.
FAU - Dear, James W
AU  - Dear JW
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK.
FAU - Dhaun, Neeraj
AU  - Dhaun N
AD  - British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical 
      Research Institute, University of Edinburgh, Edinburgh, UK; Clinical Research 
      Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK; 
      Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK. 
      Electronic address: bean.dhaun@ed.ac.uk.
LA  - eng
SI  - ClinicalTrials.gov/NCT02062346
GR  - FS/16/14/32023/BHF_/British Heart Foundation/United Kingdom
GR  - RE/18/5/34216/BHF_/British Heart Foundation/United Kingdom
GR  - CH/F/21/90010/BHF_/British Heart Foundation/United Kingdom
GR  - MR/R017840/1/MRC_/Medical Research Council/United Kingdom
GR  - SCAF/19/02/CSO_/Chief Scientist Office/United Kingdom
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20220820
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
RN  - 0 (Endothelin-1)
RN  - 0 (Receptors, Endothelin)
SB  - IM
CIN - Kidney Int. 2022 Nov;102(5):963-966. PMID: 36272753
MH  - Humans
MH  - *Vascular Stiffness
MH  - Tissue Plasminogen Activator
MH  - Fibrinolysis
MH  - Pulse Wave Analysis
MH  - *Cardiovascular Diseases/etiology
MH  - Endothelin-1
MH  - Case-Control Studies
MH  - Cross-Over Studies
MH  - Risk Factors
MH  - *Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications/drug 
      therapy
MH  - Heart Disease Risk Factors
MH  - Receptors, Endothelin
OTO - NOTNLM
OT  - ANCA vasculitis
OT  - cardiovascular risk
OT  - endothelin blockade
EDAT- 2022/08/24 06:00
MHDA- 2022/10/26 06:00
CRDT- 2022/08/23 19:26
PHST- 2021/09/27 00:00 [received]
PHST- 2022/06/20 00:00 [revised]
PHST- 2022/07/11 00:00 [accepted]
PHST- 2022/08/24 06:00 [pubmed]
PHST- 2022/10/26 06:00 [medline]
PHST- 2022/08/23 19:26 [entrez]
AID - S0085-2538(22)00633-0 [pii]
AID - 10.1016/j.kint.2022.07.026 [doi]
PST - ppublish
SO  - Kidney Int. 2022 Nov;102(5):1115-1126. doi: 10.1016/j.kint.2022.07.026. Epub 2022 
      Aug 20.