Identification and Classification of Acute Cardiac Rejection by Intragraft Transcriptional Profiling

• Authors: Cecile TJ Holweg, Stanford University; Luciano Potena, Stanford University; Helen Luikart, Stanford University; Tianwei Yu, Emory University; Gerald J Berry, Stanford University; John P Cooke, Stanford University; Hannah A Valantine, Stanford University; Edward S Mocarski, Emory University
• Journal Title: Circulation
• Volume: Volume 123, Number 20
• Publisher: American Heart Association | 2011-05-24, Pages 2236-2243
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1161/CIRCULATIONAHA.109.913921
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: heart; biopsy; transplantation; gene expression

Abstract

Background Treatment of acute rejection (AR) in heart transplantation relies on histopathological grading of endomyocardial biopsies (EMB) according to International Society for Heart and Lung Transplantation (ISHLT) guidelines. Intragraft gene expression profiling may be a way to complement histological evaluation. Methods and results Transcriptional profiling was performed on 26 EMB and expression patterns were compared with the 1990 ISHLT AR grades. Importantly, transcriptional profiles from settings with an equivalent AR grade appeared the same. In addition, grade 0 profiles could not be distinguished from 1A and grade 3A profiles could not be distinguished from 3B. Comparing the AR groupings (0+1A, 1B, and 3A+3B), 0+1A showed more striking differences from 1B than from 3A+3B. When these findings were extrapolated to the 2005 revised guidelines, the combination of 1A and 1B into a single category (1R) appears to have brought together EMBs with different underlying processes that is not evident from histological evaluation. Grade 1B was associated with upregulated immune response genes, as one categorical distinction from grade 1A. Although, grade 1B was distinct from the clinically relevant AR grades 3A and 3B, all of these grades shared a small number of overlapping pathways consistent with common physiological underpinnings. Conclusion The gene expression similarities and differences identified here in different AR settings have the potential to revise the clinical perspective on acute graft rejection, pending the results of larger studies.