title: Determinants and Outcomes of Accelerated Arteriosclerosis: Major Impact of Circulating Antibodies.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From 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.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Loupy
authors.affiliation: From 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.
authors.forename: Dewi
authors.initials: D
authors.lastname: Vernerey
authors.affiliation: From 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.
authors.forename: Denis
authors.initials: D
authors.lastname: Viglietti
authors.affiliation: From 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Aubert
authors.affiliation: From 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.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Duong Van Huyen
authors.affiliation: From 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.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Empana
authors.affiliation: From 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: From 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.
authors.forename: Denis
authors.initials: D
authors.lastname: Glotz
authors.affiliation: From 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.affiliation: From 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jouven
authors.affiliation: From 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lefaucheur
mesh_terms: D000328:Adult; D000368:Aged; D001161:Arteriosclerosis / Q000097:blood* / Q000175:diagnosis* / Q000601:surgery; D001323:Autoantibodies / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis; D006085:Graft Survival / Q000502:physiology*; D006680:HLA Antigens / Q000097:blood; D006801:Humans; D016030:Kidney Transplantation / Q000639:trends*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014184:Transplantation, Homologous / Q000639:trends; D016896:Treatment Outcome
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens
keywords: antibodies; arteriosclerosis; cardiovascular diseases; transplantation