Clinical Implications and Longitudinal Alteration of Peripheral Blood Transcriptional Signals Indicative of Future Cardiac Allograft Rejection

Mandeep R. Mehra, Jon A. Kobashigawa, Mario C. Deng, Kenneth C. Fang, Tod M. Klingler, Preeti G. Lal, Steven Rosenberg, Patricia A. Uber, Randall C. Starling, Srinivas Murali, Daniel F. Pauly, Russell Dedrick, Michael G. Walker, Adriana Zeevi, Howard Eisen

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: We have previously demonstrated that a peripheral blood transcriptional profile using 11 distinct genes predicts onset of cardiac allograft rejection weeks to months prior to the actual event. Methods: In this analysis, we ascertained the performance of this transcriptional algorithm in a Bayesian representative population: 28 cardiac transplant recipients who progressed to moderate to severe rejection; 53 who progressed to mild rejection; and 46 who remained rejection-free. Furthermore, we characterized longitudinal alterations in the transcriptional gene expression profile before, during and after recovery from rejection. Results: In this patient cohort, we found that a gene expression score (range 0 to 40) of ≤20 represents very low risk of rejection in the subsequent 12 weeks: 0 progressed to treatable (ISHLT Grade ≥3A) rejection; 16 of 53 (30%) from the intermediate group (those who progressed to ISHLT Grade 1B or 2) and 13 of 46 (28%) controls (who remained Grade 0 or 1A) had scores ≤20. A gene score of ≥30 was associated with progression to moderate to severe rejection in 58% of cases. These two extreme scores (≤20 or ≥30) represented 44% of the cardiac transplant population within 6 months post-transplant. In addition, longitudinal gene expression analysis demonstrated that baseline scores were significantly higher for those who went on to reject, remained high during an episode of rejection, and dropped post-treatment for rejection (p < 0.01). Conclusions: The use of gene expression profiling early after transplantation allows for separation into low-, intermediate- or high-risk categories for future rejection, permitting development of discrete surveillance strategies.

Original languageEnglish (US)
Pages (from-to)297-301
Number of pages5
JournalJournal of Heart and Lung Transplantation
Volume27
Issue number3
DOIs
StatePublished - Mar 1 2008

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Allografts
Transplants
Gene Expression
Gene Expression Profiling
Transcriptome
Population
Genes
Transplantation
Therapeutics
Transplant Recipients

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Mehra, Mandeep R. ; Kobashigawa, Jon A. ; Deng, Mario C. ; Fang, Kenneth C. ; Klingler, Tod M. ; Lal, Preeti G. ; Rosenberg, Steven ; Uber, Patricia A. ; Starling, Randall C. ; Murali, Srinivas ; Pauly, Daniel F. ; Dedrick, Russell ; Walker, Michael G. ; Zeevi, Adriana ; Eisen, Howard. / Clinical Implications and Longitudinal Alteration of Peripheral Blood Transcriptional Signals Indicative of Future Cardiac Allograft Rejection. In: Journal of Heart and Lung Transplantation. 2008 ; Vol. 27, No. 3. pp. 297-301.
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title = "Clinical Implications and Longitudinal Alteration of Peripheral Blood Transcriptional Signals Indicative of Future Cardiac Allograft Rejection",
abstract = "Background: We have previously demonstrated that a peripheral blood transcriptional profile using 11 distinct genes predicts onset of cardiac allograft rejection weeks to months prior to the actual event. Methods: In this analysis, we ascertained the performance of this transcriptional algorithm in a Bayesian representative population: 28 cardiac transplant recipients who progressed to moderate to severe rejection; 53 who progressed to mild rejection; and 46 who remained rejection-free. Furthermore, we characterized longitudinal alterations in the transcriptional gene expression profile before, during and after recovery from rejection. Results: In this patient cohort, we found that a gene expression score (range 0 to 40) of ≤20 represents very low risk of rejection in the subsequent 12 weeks: 0 progressed to treatable (ISHLT Grade ≥3A) rejection; 16 of 53 (30{\%}) from the intermediate group (those who progressed to ISHLT Grade 1B or 2) and 13 of 46 (28{\%}) controls (who remained Grade 0 or 1A) had scores ≤20. A gene score of ≥30 was associated with progression to moderate to severe rejection in 58{\%} of cases. These two extreme scores (≤20 or ≥30) represented 44{\%} of the cardiac transplant population within 6 months post-transplant. In addition, longitudinal gene expression analysis demonstrated that baseline scores were significantly higher for those who went on to reject, remained high during an episode of rejection, and dropped post-treatment for rejection (p < 0.01). Conclusions: The use of gene expression profiling early after transplantation allows for separation into low-, intermediate- or high-risk categories for future rejection, permitting development of discrete surveillance strategies.",
author = "Mehra, {Mandeep R.} and Kobashigawa, {Jon A.} and Deng, {Mario C.} and Fang, {Kenneth C.} and Klingler, {Tod M.} and Lal, {Preeti G.} and Steven Rosenberg and Uber, {Patricia A.} and Starling, {Randall C.} and Srinivas Murali and Pauly, {Daniel F.} and Russell Dedrick and Walker, {Michael G.} and Adriana Zeevi and Howard Eisen",
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Mehra, MR, Kobashigawa, JA, Deng, MC, Fang, KC, Klingler, TM, Lal, PG, Rosenberg, S, Uber, PA, Starling, RC, Murali, S, Pauly, DF, Dedrick, R, Walker, MG, Zeevi, A & Eisen, H 2008, 'Clinical Implications and Longitudinal Alteration of Peripheral Blood Transcriptional Signals Indicative of Future Cardiac Allograft Rejection', Journal of Heart and Lung Transplantation, vol. 27, no. 3, pp. 297-301. https://doi.org/10.1016/j.healun.2007.11.578

Clinical Implications and Longitudinal Alteration of Peripheral Blood Transcriptional Signals Indicative of Future Cardiac Allograft Rejection. / Mehra, Mandeep R.; Kobashigawa, Jon A.; Deng, Mario C.; Fang, Kenneth C.; Klingler, Tod M.; Lal, Preeti G.; Rosenberg, Steven; Uber, Patricia A.; Starling, Randall C.; Murali, Srinivas; Pauly, Daniel F.; Dedrick, Russell; Walker, Michael G.; Zeevi, Adriana; Eisen, Howard.

In: Journal of Heart and Lung Transplantation, Vol. 27, No. 3, 01.03.2008, p. 297-301.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Clinical Implications and Longitudinal Alteration of Peripheral Blood Transcriptional Signals Indicative of Future Cardiac Allograft Rejection

AU - Mehra, Mandeep R.

AU - Kobashigawa, Jon A.

AU - Deng, Mario C.

AU - Fang, Kenneth C.

AU - Klingler, Tod M.

AU - Lal, Preeti G.

AU - Rosenberg, Steven

AU - Uber, Patricia A.

AU - Starling, Randall C.

AU - Murali, Srinivas

AU - Pauly, Daniel F.

AU - Dedrick, Russell

AU - Walker, Michael G.

AU - Zeevi, Adriana

AU - Eisen, Howard

PY - 2008/3/1

Y1 - 2008/3/1

N2 - Background: We have previously demonstrated that a peripheral blood transcriptional profile using 11 distinct genes predicts onset of cardiac allograft rejection weeks to months prior to the actual event. Methods: In this analysis, we ascertained the performance of this transcriptional algorithm in a Bayesian representative population: 28 cardiac transplant recipients who progressed to moderate to severe rejection; 53 who progressed to mild rejection; and 46 who remained rejection-free. Furthermore, we characterized longitudinal alterations in the transcriptional gene expression profile before, during and after recovery from rejection. Results: In this patient cohort, we found that a gene expression score (range 0 to 40) of ≤20 represents very low risk of rejection in the subsequent 12 weeks: 0 progressed to treatable (ISHLT Grade ≥3A) rejection; 16 of 53 (30%) from the intermediate group (those who progressed to ISHLT Grade 1B or 2) and 13 of 46 (28%) controls (who remained Grade 0 or 1A) had scores ≤20. A gene score of ≥30 was associated with progression to moderate to severe rejection in 58% of cases. These two extreme scores (≤20 or ≥30) represented 44% of the cardiac transplant population within 6 months post-transplant. In addition, longitudinal gene expression analysis demonstrated that baseline scores were significantly higher for those who went on to reject, remained high during an episode of rejection, and dropped post-treatment for rejection (p < 0.01). Conclusions: The use of gene expression profiling early after transplantation allows for separation into low-, intermediate- or high-risk categories for future rejection, permitting development of discrete surveillance strategies.

AB - Background: We have previously demonstrated that a peripheral blood transcriptional profile using 11 distinct genes predicts onset of cardiac allograft rejection weeks to months prior to the actual event. Methods: In this analysis, we ascertained the performance of this transcriptional algorithm in a Bayesian representative population: 28 cardiac transplant recipients who progressed to moderate to severe rejection; 53 who progressed to mild rejection; and 46 who remained rejection-free. Furthermore, we characterized longitudinal alterations in the transcriptional gene expression profile before, during and after recovery from rejection. Results: In this patient cohort, we found that a gene expression score (range 0 to 40) of ≤20 represents very low risk of rejection in the subsequent 12 weeks: 0 progressed to treatable (ISHLT Grade ≥3A) rejection; 16 of 53 (30%) from the intermediate group (those who progressed to ISHLT Grade 1B or 2) and 13 of 46 (28%) controls (who remained Grade 0 or 1A) had scores ≤20. A gene score of ≥30 was associated with progression to moderate to severe rejection in 58% of cases. These two extreme scores (≤20 or ≥30) represented 44% of the cardiac transplant population within 6 months post-transplant. In addition, longitudinal gene expression analysis demonstrated that baseline scores were significantly higher for those who went on to reject, remained high during an episode of rejection, and dropped post-treatment for rejection (p < 0.01). Conclusions: The use of gene expression profiling early after transplantation allows for separation into low-, intermediate- or high-risk categories for future rejection, permitting development of discrete surveillance strategies.

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