title: Cardiac transplant-associated vascular disease: Evolution, immunophenotype, and evidence of endothelial activation.
abstract: Transplant-associated vascular disease (TAVD) is a major cause of late mortality after cardiac transplantation. To elucidate the evolution of TAVD, the autopsy histopathology of five cardiac allograft recipients who died ≥12 months posttransplantation was studied semiquantitatively. Vessel cross sections were analyzed for size, proliferative lesions, inflammation, lipid, and thrombi. The type of inflammatory cells in the vessels were characterized by immunohistochemistry, and the activation state of the vessel endothelium was characterized by immunohistochemistry for HLA-DR and inducible endothelial leukocyte adhesion proteins [endothelial leukocyte adhesion molecule-1 (SLAM-1) and vascular cell adhesion molecule-1 (VCAM-1)]. The mean posttransplantation interval was 27.2 months (range 12-40). TAVD was present in all five patients and was the cause of death in four of five. The percentage of vessels with proliferative lesions increased progressively with the duration of survival after transplantation. Both arteries and veins contained proliferative lesions, but more arteries than veins were involved at all time points. Large veins and large arteries had a significantly higher proportion of proliferative lesions than small veins (p < 0.04) and small arteries (p < 0.06), respectively. Inflammatory lesions were more prevalent in arteries than veins, 55.7% versus 10.9% (p < 0.001). The inflammatory vascular lesions were comprised principally of T lymphocytes, with smaller numbers of B lymphocytes and macrophages. The endothelium of arteries and veins expressed HLA-DR as well as VCAM-1, but stains for ELAM-1 showed only focal expression. By linear regression, intimal/medial inflammation decreased with time (r = -0.81, p < 0.06) and adventitial inflammation increased with time (r = +0.98, p < 0.001). Lipid-containing lesions were observed in 13.0% of arterial cross sections and were not seen in veins. Lipid containing arterial lesions increased progressively with both time and vessel size, but, in contrast to proliferative and inflammatory lesions, were not seen at any time interval in veins or small arteries. In summary, TAVD is an inflammatory and proliferative process that involves arteries more than veins, and is more prevalent in large vessels and at greater posttransplantation intervals. Vascular T cell inflammation, intimal proliferation, and an activated endothelial cell phenotype appear to be closely related in the development of TAVD.
authors.affiliation: Department of Laboratory Hematology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kottke-Marchant
authors.affiliation: Otsuka America Pharmaceutical Co., Rockville, Maryland, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Newman
authors.affiliation: Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: N B
authors.initials: NB
authors.lastname: Ratliff