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Transplant-related coronary-artery disease (TCAD) develops frequently in cardiac-allograft recipients, and limits long-term survival. We examined the relation between this disorder and cumulative frequency of high-grade rejection, and investigated whether concomitant use of three immunological factors at the time of a low-grade endomyocardial biopsy can predict progression to high-grade rejection.We investigated the relation between the cumulative annual frequency of high-grade rejection and TCAD in 198 recipients of cardiac transplantation between 1992 and 1996 by means of Kaplan-Meier actuarial life-tables. Endomyocardial biopsy, lymphocyte-growth assays, and anti-HLA antibody measurements were compiled over 12 months in 102 patients during their first post-transplant year. We calculated predictive values for high-grade rejection within 90 days by chi2, Kaplan Meier survival curves, and by multivariable logistic regression analyses.We found a direct correlation between cumulative annual frequency of rejection and TCAD onset with highest risk in those with more than 0.75 rejections per year (p=0.0002). After a low-grade endomyocardial biopsy (0 or 1A), one or more donor-recipient HLA-DR matches protected against high-grade rejections (p0.001). Among individuals with one or two DR matches, the negative predictive value for progression from a low-grade biopsy to a high-grade rejection was 87% in the presence of a negative lymphocyte-growth assay. Among individuals with no DR matches, the presence of either a positive lymphocyte-growth assay or IgG anti-major-histocompatibility complex (MHC) class II antibodies was independently associated with high probability of progression to rejection (64% and 66%, respectively, p0.0005). When both assays were positive, concomitantly with a low-grade endomyocardial biopsy, the positive predictive value for progression to a high-grade rejection was 86% (p0.0001). For endomyocardial-biopsy grades 1B or 2, a positive lymphocyte-growth assay alone was associated with high-grade rejection in 100% of cases.Use of an algorithm combining three immunological factors at the time of a low-grade endomyocardial biopsy enables prospective stratification of cardiac transplant recipients into risk categories for progression to high-grade rejection. Low-risk individuals require fewer biopsies, moderate-risk individuals require an ongoing schedule of surveillance biopsies, and high-risk individuals require rational organisation of interventional strategies aimed at preventing rejection. Additional predictive factors are needed to identify moderate-risk individuals who will progress to rejection. Ultimately, successful intervention may have an impact on the subsequent complication of TCAD.