Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters.
BACKGROUND
As acute cellular cardiac allograft rejection is a systemic process affecting the entire organism, we hypothesized that scores of a peripheral blood mononuclear cell gene expression profiling (GEP) test developed and validated to rule out International Society of Heart and Lung Transplantation (ISHLT) grade > or = 3A/2R acute cellular cardiac allograft rejection also reflects biologically plausible changes of the routinely assessed clinical parameters.


METHODS
We retrospectively analyzed 76 patients who underwent GEP testing, at the time of their routine clinical follow-up in our Institution between February 1, 2006 and January 31, 2007. Data were analyzed with t-test, nonparametric tests, bivariate Spearman's correlation, and multivariate linear regression modeling.


RESULTS
More activated GEP-score correlated with longer corrected QT (QTc)-interval (r = 0.377, p = 0.001, n = 63), longer QRS duration (r = 0.231, p = 0.03, n = 66), higher heart rate (r = 0.221, p = 0.037, n = 66), higher serum creatinine (r = 0.26, p = 0.01, n = 75), higher gamma-glutamyl transferase (GGT) GGT (r = 0.266, p = 0.037, n = 46), lower pulmonary artery oxygen saturation (r = -0.313, p = 0.003, n = 76), lower platelet count (r = -0.372, p = 0.001, n = 74), lower monocyte count (r = -0.208, p = 0.040, n = 72), and lower high-density lipoprotein (HDL) HDL level (r = -0.242, p = 0.041, n = 53). Multivariate analysis showed a significant amount of variance in the GEP score independently explained by the variability of QTc-interval (beta = 1.998, p = 0.001) and platelet count (beta = -1.540, p = 0.017). Post hoc analysis of the 11 individual GEP-classifier genes showed WDRA40 (p = 0.02) and ras homolog gene family, member U (RHOU) RHOU (p = 0.01) independently related to mixed venous O(2)Sat%.


CONCLUSIONS
A GEP test developed and validated to detect the absence of cardiac rejection correlates with electrocardiographic and hemodynamic cardiac parameters as well as renal, hepatic, bone marrow, and lipid metabolism parameters suggesting a complex relationship between rejection, leukocytes, and organ function within the continuum between alloimmunological quiescence and rejection.
Cadeiras
Martin
M
Department of Medicine, Division of Cardiology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
Shahzad
Khurram
K
John
Manju M
MM
Gruber
Dorota
D
Bayern
Manuel von
Mv
Auerbach
Scott
S
Sinha
Anshu
A
Latif
Farhana
F
Unniachan
Sreevalsa
S
Memon
Sarfaraz
S
Mital
Seema
S
Restaino
Susan
S
Marboe
Charles C
CC
Addonizio
Linda J
LJ
Deng
Mario C
MC
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000175:diagnosis* / Q000235:genetics*; D006321:Heart / Q000502:physiology*; D016027:Heart Transplantation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012189:Retrospective Studies; D055815:Young Adult
D015415:Biomarkers