Concordance among pathologists in the second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II).

BACKGROUND: There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). METHODS: We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers). RESULTS: Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both. CONCLUSION: The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria--EMB based or otherwise--that correspond better with the pathophysiology of the transplanted heart.

Cellular coating of the left ventricular assist device textured polyurethane membrane reduces adhesion of Staphylococcus aureus.

OBJECTIVE: Infections are among the most common and serious complications of ventricular assist device implantation. These infections generally occur within the first 2 months after surgery. The basis for this high incidence of infection is not well established, so a murine intravascular infection model was developed with aortic implantation of the textured polyurethane patch material currently used in HeartMate ventricular assist devices (Thoratec Corporation Pleasanton, Calif). METHODS: Polyurethane patch material was placed in the wall of the mouse descending aorta. Mice were then infected with Staphylococcus aureus 1 or 14 days after implantation. In vitro adhesion studies were conducted with polyurethane membranes coated with endothelial cells and membranes coated with fibrinogen. RESULTS: Mice were susceptible to infection in both dose- and time-dependent fashions. The patch material was significantly more susceptible to infection at day 1 than day 14. Immunohistologic and morphologic studies demonstrated that the CD31+ cells deposited on the membrane surface phenotypically appeared to be endothelial cells. In vitro adhesion studies of polyurethane membranes coated with endothelial cells showed them to be less susceptible to S. aureus binding than were membranes coated with fibrinogen. CONCLUSION: Textured polyurethane membranes are less susceptible to infection as cellular deposition occurs. The time frame within which these membranes become populated with cellular material is consistent with the time-dependent clinical incidence of infection. Cellular coating of polyurethane may provide a strategy for reducing the risk of infection.

The role of Staphylococcus aureus adhesins in the pathogenesis of ventricular assist device-related infections.

Ventricular assist devices (VADs) are an important form of therapy for end-stage congestive heart failure. However, infection of the VAD, which is often caused by Staphylococcus aureus, poses a major threat to survival. Using a novel in vitro binding assay with VAD membranes and a heterologous lactococcal system of expression, we identify 3 S. aureus proteins--clumping factor A (ClfA) and fibronectin binding proteins A and B (FnBPA and FnBPB) as the main factors involved in adherence to VAD polyurethane membranes. Adherence is greatly diminished by long implantation times, reflecting a change in topological features of the VAD membrane, and is primarily mediated by the FnBPA domains in the staphylococcal proteins. We also compare the adherence of S. aureus mutant strains and show that other staphylococcal components appear to be involved in adherence to VAD membranes. Finally, we demonstrate that ClfA, FnBPA, and FnBPB mediate bacterial infection of implanted murine intra-aortic polyurethane patches.

The economic implications of noninvasive molecular testing for cardiac allograft rejection.

Endomyocardial biopsy is the mainstay for monitoring cardiac allograft rejection. A noninvasive strategy--peripheral blood gene expression profiling of circulating leukocytes--is an alternative with proven benefits, but unclear economic implications. Financial data were obtained from five cardiac transplant centers. An economic evaluation was conducted to compare the costs of outpatient biopsy with those of a noninvasive approach to monitoring cardiac allograft rejection. Hospital outpatient biopsy costs averaged 3297 US dollars, excluding reimbursement for professional fees. Costs to Medicare and private payers averaged 3581 US dollars and 4140 US dollars, respectively. A noninvasive monitoring test can reduce biopsy utilization. The savings to health care payers in the United States can be conservatively estimated at approximately 12.0 million US dollars annually. Molecular testing using gene expression profiling of peripheral circulating leukocytes is a new technology that offers physicians a noninvasive, less expensive alternative to endomyocardial biopsy for monitoring allograft rejection in cardiac transplant patients.