Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters

Martin Cadeiras, Khurram Shahzad, Manju M. John, Dorota Gruber, Manuel von Bayern, Scott Auerbach, Anshu Sinha, Farhana Latif, Sreevalsa Unniachan, Sarfaraz Memon, Seema Mital, Susan Restaino, Charles C. Marboe, Linda J. Addonizio, Mario C. Deng

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 ≥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 (β = 1.998, p = 0.001) and platelet count (β = -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 O2Sat%. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)321-327
Number of pages7
JournalClinical Transplantation
Volume24
Issue number3
DOIs
StatePublished - May 1 2010
Externally publishedYes

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Graft Rejection
Gene Expression Profiling
HDL Lipoproteins
Transferases
Platelet Count
Allografts
Heart-Lung Transplantation
ras Genes
Lipid Metabolism
Pulmonary Artery
Monocytes
Linear Models
Blood Cells
Creatinine
Leukocytes
Multivariate Analysis
Heart Rate
Hemodynamics
Bone Marrow
Oxygen

Keywords

  • Electrocardiography
  • Gene expression
  • Heart transplantation
  • Hemodynamics
  • Molecular testing

ASJC Scopus subject areas

  • Transplantation

Cite this

Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters. / Cadeiras, Martin; Shahzad, Khurram; John, Manju M.; Gruber, Dorota; Bayern, Manuel von; Auerbach, Scott; Sinha, Anshu; Latif, Farhana; Unniachan, Sreevalsa; Memon, Sarfaraz; Mital, Seema; Restaino, Susan; Marboe, Charles C.; Addonizio, Linda J.; Deng, Mario C.

In: Clinical Transplantation, Vol. 24, No. 3, 01.05.2010, p. 321-327.

Research output: Contribution to journalArticle

Cadeiras, M, Shahzad, K, John, MM, Gruber, D, Bayern, MV, Auerbach, S, Sinha, A, Latif, F, Unniachan, S, Memon, S, Mital, S, Restaino, S, Marboe, CC, Addonizio, LJ & Deng, MC 2010, 'Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters', Clinical Transplantation, vol. 24, no. 3, pp. 321-327. https://doi.org/10.1111/j.1399-0012.2009.01063.x
Cadeiras, Martin ; Shahzad, Khurram ; John, Manju M. ; Gruber, Dorota ; Bayern, Manuel von ; Auerbach, Scott ; Sinha, Anshu ; Latif, Farhana ; Unniachan, Sreevalsa ; Memon, Sarfaraz ; Mital, Seema ; Restaino, Susan ; Marboe, Charles C. ; Addonizio, Linda J. ; Deng, Mario C. / Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters. In: Clinical Transplantation. 2010 ; Vol. 24, No. 3. pp. 321-327.
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T1 - Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters

AU - Cadeiras, Martin

AU - Shahzad, Khurram

AU - John, Manju M.

AU - Gruber, Dorota

AU - Bayern, Manuel von

AU - Auerbach, Scott

AU - Sinha, Anshu

AU - Latif, Farhana

AU - Unniachan, Sreevalsa

AU - Memon, Sarfaraz

AU - Mital, Seema

AU - Restaino, Susan

AU - Marboe, Charles C.

AU - Addonizio, Linda J.

AU - Deng, Mario C.

PY - 2010/5/1

Y1 - 2010/5/1

N2 - 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 ≥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 (β = 1.998, p = 0.001) and platelet count (β = -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 O2Sat%. Conclusion: 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.

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KW - Electrocardiography

KW - Gene expression

KW - Heart transplantation

KW - Hemodynamics

KW - Molecular testing

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