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(Circulation. 2004;110:3815-3821.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Detection of Cardiac Allograft Rejection and Response to Immunosuppressive Therapy With Peripheral Blood Gene Expression

Phillip A. Horwitz, MD; Emily J. Tsai, MD; Mary E. Putt, ScD, PhD; Joan M. Gilmore, BS; John J. Lepore, MD; Michael S. Parmacek, MD; Andrew C. Kao, MD; Shashank S. Desai, MD; Lee R. Goldberg, MD, MPH; Susan C. Brozena, MD; Mariell L. Jessup, MD; Jonathan A. Epstein, MD; Thomas P. Cappola, MD, ScM

From the Department of Internal Medicine, Division of Cardiovascular Diseases, University of Iowa–Roy J. and Lucille A. Carver College of Medicine (P.A.H.), Iowa City, Iowa; Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine (E.J.T., J.M.G., J.J.L., M.S.P., A.C.K., S.S.D., L.R.G., S.C.B., M.L.J., J.A.E., T.P.C.), Philadelphia, Pa; and Division of Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania (M.E.P.), Philadelphia, Pa.

Correspondence to Thomas P. Cappola, MD, ScM, Heart Failure and Transplantation, Division of Cardiovascular Medicine, 6 Penn Tower, 3400 Spruce St, Philadelphia, PA 19104. E-mail thomas.cappola{at}uphs.upenn.edu

Received June 29, 2004; revision received September 28, 2004; accepted October 15, 2004.

Background— Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes.

Methods and Results— We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944).

Conclusions— These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB.

Key Words: immune system • transplantation • rejection • genes • diagnosis

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