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Determinants and Outcomes of Accelerated Arteriosclerosis: Major Impact of Circulating Antibodies
Alexandre Loupy1, Dewi Vernerey2, Denis Viglietti2
1From the Paris Translational Research Center for Organ Transplantation and Cardiovascular Disease, INSERM, UMR-S970, Paris, France (A.L., D. Viglietti, O.A., J.-P.D.V.H., J.-P.E., P.B., D.G., C. Legendre, X.J., C. Lefaucheur); Paris Descartes University, Sorbonne Paris Cité and Necker Hospital (A.L., J.-P.D.V.H., C. Legendre) and Department of Transplantation, Saint-Louis Hospital (D. Viglietti, D.G., C. Lefaucheur), Assistance Publique - Hôpitaux de Paris, Paris, France; Methodology Unit (EA 3181) CHRU de Besançon, Besançon, France (D. Vernerey); Department of Pathology, Necker Hospital, Paris, France (J.-P.D.V.H.); and Department of Pathology (P.B.) and Department of Cardiology (X.J.), Georges Pompidou European Hospital, Paris, France. alexandreloupy@gmail.com.
Insights
Circulating anti-human leukocyte antigen (HLA) antibodies significantly accelerate arteriosclerosis in kidney transplant patients. These antibodies increase the risk of graft loss and major adverse cardiovascular events, independent of traditional risk factors.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Transplantation Science
Background:
- The role of circulating antibodies in accelerated arteriosclerosis and their clinical consequences remains under-investigated.
- Traditional cardiovascular risk factors alone may not fully explain arteriosclerosis development post-transplant.
Purpose of the Study:
- To investigate the impact of circulating antibodies on accelerated arteriosclerosis in kidney transplant recipients.
- To determine the association between immune-mediated arteriosclerosis and graft/patient survival.
- To evaluate the link between immune-associated arteriosclerosis and major adverse cardiovascular events (MACE).
Main Methods:
- Observational prospective cohort study of 1065 kidney transplant patients (2004-2010).
- Assessment of traditional cardiovascular risk factors and circulating anti-human leukocyte antigen (HLA) antibodies.
- Allograft biopsies analyzed for arteriosclerosis, endothelial activation, endarteritis, and complement deposition.
Main Results:
- Severe arteriosclerosis (fibrointimal thickening >25%) found in 33.6% of patients.
- Donor-specific anti-HLA antibodies strongly associated with severe allograft arteriosclerosis (HR 2.9, P<0.0001), independent of traditional risk factors.
- Antibody-associated severe arteriosclerosis linked to reduced allograft survival, increased mortality, and significantly higher risk of MACE (2.5-4.1 fold increase).
- Circulating donor-specific anti-HLA antibodies independently predicted MACE (HR 2.4, P=0.0004).
Conclusions:
- Circulating antibodies are critical determinants of severe arteriosclerosis in kidney transplant recipients.
- Immune-mediated arteriosclerosis significantly impacts graft survival, patient mortality, and cardiovascular events.
- Anti-HLA antibodies represent a key factor in cardiovascular risk, beyond traditional risk factors.
Rationale:
The role of circulating antibodies in addition to traditional cardiovascular risk factors in the development of accelerated arteriosclerosis and their long-term clinical consequences have not been demonstrated.
Objective:
We investigated the role of circulating antibodies in accelerated arteriosclerosis and the role of immune-associated arteriosclerosis in graft and patient survival and the occurrence of major adverse cardiovascular events.
Methods And Results:
This was an observational prospective cohort study that included 1065 kidney transplant patients (principal cohort, n=744; validation cohort, n=321) between 2004 and 2010. Participants were assessed for traditional cardiovascular risk factors and circulating anti-human leukocyte antigen (HLA) antibodies. All patients underwent allograft biopsies to assess arteriosclerotic lesions and endothelial activation, endarteritis, and complement deposition. In the principal cohort, 250 (33.6%) patients had severe arteriosclerosis (luminal narrowing >25% via fibrointimal arterial thickening). Circulating donor-specific anti-HLA antibodies were significantly associated with severe allograft arteriosclerosis (hazard ratio, 2.9; P<0.0001), independently of traditional risk factors. Patients with severe arteriosclerosis and anti-HLA antibodies (n=91, 12.2%) demonstrated allograft endothelial activation, endarteritis, and complement deposition. High levels of anti-HLA antibodies and their complement binding capacity were associated with increased severity of arteriosclerosis. Patients with antibody-associated severe arteriosclerosis had decreased allograft survival and increased mortality (P<0.0001); they exhibited a 2.5- and 4.1-fold increased risk of major adverse cardiovascular events compared with patients who had severe arteriosclerosis without antibodies and patients with minimal arteriosclerosis, respectively (P<0.0005). Circulating donor-specific anti-HLA antibodies were significantly associated with occurrence of major adverse cardiovascular events (hazard ratio, 2.4; P=0.0004), independently of traditional risk factors.
Conclusions:
Circulating antibodies are major determinants of severe arteriosclerosis and major adverse cardiovascular events, independent of traditional cardiovascular risk factors.
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