Determinants and Outcomes of Accelerated Arteriosclerosis: Major Impact of Circulating Antibodies

Abstract

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 (MACE).

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-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 (HR=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 MACE 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 MACE (HR=2.4, p=0.0004), independently of traditional risk factors.

Conclusions: Circulating antibodies are major determinants of severe arteriosclerosis and MACE, independent of traditional cardiovascular risk factors.