Correlating Microarray Gene Expression Data with Histopathology in Human Heart Allograft Biopsies
M Mengel, J Chang, D Kim, B Sis, J Reeve, J Burton, W Tymchak, P Halloran. University of Alberta, Edmonton, Canada
Background: The histopathological criteria for assessing endomyocardial biopsies are empiric and arbitrary lacking external biological validation. Aim was to correlate gene expression with histopathological lesions and diagnosis based on ISHLT criteria in human heart allograft biopsies.
Design: We performed histologic and microarray analysis on 105 endomyocardial biopsies from 45 heart allograft recipients. We included 82 protocol biopsies (PB) and 23 biopsies done for clinical causes (BFC), 70 obtained within the first year after transplantation and 35 taken later. Genome-wide expression data were correlated as pathogenesis-based transcript (PBTs) sets to histological lesions and diagnosis as well as to left ventricular ejection fraction (LVEF). PBTs are a priori defined gene sets reflecting major biological processes in allografts, e.g. T cell infiltration, myocyte dedifferentiation. Groups of related correlations were identified by cluster analysis.
Results: There was strong stereotyping of molecular changes: inflammation (T cell, macrophage, IFNG effects) strongly correlated with increased expression of injury induced genes and decreased expression of genes associated with myocyte function. The changes were greater in BFC and in early biopsies than in PB and late biopsies. Expression of transcripts associated with B cells and immunoglobulins strongly correlated with time post transplant and with presence of Quilty type B lesions. LVEF was lower in biopsies with higher molecular disturbances, including transcripts associated with myocyte injury. Histological lesions most correlated with high PBT scores were interstitial edema, hemorrhage, and capillaritis. The current histologic criteria for acute cellular rejection, i.e. interstitial infiltrates and myocytolysis – showed no association with the molecular features of the biopsy. The molecular burden of inflammation and loss of myocyte function associated transcripts was most closely correlated with Quilty type B lesions but not with other ISHLT diagnosis.
Conclusions: We conclude that measurement of transcriptome abnormalities reflects a stereotyped disturbance in the endomyocardium with an increase in inflammation/injury and decrease in myocytal transcripts, that translates into impaired function and pathologic lesions, but not current ISHLT categories for rejection.
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 34, Wednesday Afternoon