The Journal of Heart and Lung Transplantation
Volume 23, Issue 6 , Pages 701-708, June 2004

Heart allograft rejection: detection with breath alkanes in low levels (the HARDBALL study)☆

This study was presented as a Late Breaking Clinical Trial at the American College of Cardiology 51st Annual Scientific Session, Atlanta, GA, March 19, 2002.

  • Michael Phillips, MD, FACP

      Affiliations

    • Menssana Research, Inc. Fort Lee, New Jersey, USA
    • Department of Medicine, New York Medical College, Valhalla, New York, USA
    • Corresponding Author InformationReprint requests: Michael Phillips, MD, FACP, Menssana Research, Inc., 1 Horizon Road, Suite 1415, Fort Lee, NJ 07024, USA.
    • ,
  • John P Boehmer, MD

      Affiliations

    • Department of Medicine, M.S. Hershey Medical Center of the Pennsylvania State University School of Medicine, Hershey, Pennsylvania, USA
    • ,
  • Renee N Cataneo, MA

      Affiliations

    • Menssana Research, Inc. Fort Lee, New Jersey, USA
    • ,
  • Taseer Cheema, MD

      Affiliations

    • Menssana Research, Inc. Fort Lee, New Jersey, USA
    • ,
  • Howard J Eisen, MD

      Affiliations

    • Temple University Hospital, Philadelphia, Pennsylvania, USA
    • ,
  • John T Fallon, MD, PhD, FAHA

      Affiliations

    • Department of Pathology, Mount Sinai Medical Center, New York, USA
    • ,
  • Peter E Fisher, MD

      Affiliations

    • Columbia Presbyterian Medical Center, New York, New York, USA
    • ,
  • Alan Gass, MD

      Affiliations

    • Department of Medicine, Mount Sinai Medical Center, New York, New York, USA
    • ,
  • Joel Greenberg, BS

      Affiliations

    • Menssana Research, Inc. Fort Lee, New Jersey, USA
    • ,
  • Jon Kobashigawa, MD

      Affiliations

    • University of California Los Angeles Medical Center, Los Angeles, California, USA
    • ,
  • Donna Mancini, MD

      Affiliations

    • Columbia Presbyterian Medical Center, New York, New York, USA
    • ,
  • Barry Rayburn, MD

      Affiliations

    • University of Alabama at Birmingham, Birmingham, Alabama, USA
    • ,
  • Mark J Zucker, MD

      Affiliations

    • Newark Beth Israel Medical Center, Newark, New Jersey, USA

Received 22 January 2003; received in revised form 18 July 2003; accepted 23 July 2003.

Abstract 

Background

We evaluated a new marker of heart transplant rejection, the breath methylated alkane contour (BMAC). Rejection is accompanied by oxidative stress that degrades membrane polyunsaturated fatty acids, evolving alkanes and methylalkanes, which are excreted in the breath as volatile organic compounds (VOCs).

Methods

Breath VOC samples (n = 1,061) were collected from 539 heart transplant recipients before scheduled endomyocardial biopsy. Breath VOCs were analyzed by gas chromatography and mass spectroscopy, and BMAC was derived from the abundance of C4–C20 alkanes and monomethylalkanes. The “gold standard” of rejection was the concordant set of International Society for Heart and Lung Transplantation (ISHLT) grades in biopsies read by 2 reviewers.

Results

Concordant biopsies were: Grade 0, 645 of 1,061 (60.8%); 1A, 197 (18.6%); 1B, 84 (7.9%); 2, 93 (8.8%); and 3A, 42 (4.0%). A combination of 9 VOCs in the BMAC identified Grade 3 rejection (sensitivity 78.6%, specificity 62.4%, cross-validated sensitivity 59.5%, cross-validated specificity 58.8%, positive predictive value 5.6%, negative predictive value 97.2%). Site pathologists identified the same cases with sensitivity of 42.4%, specificity 97.0%, positive predictive value 45.2% and negative predictive value 96.7%.

Conclusions

A breath test for markers of oxidative stress was more sensitive and less specific for Grade 3 heart transplant rejection than a biopsy reading by a site pathologist, but the negative predictive values of the 2 tests were similar. A screening breath test could potentially identify transplant recipients at low risk of Grade 3 rejection and reduce the number of endomyocardial biopsies.

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☆ Michael Phillips is president of Menssana Research, Inc., and holds patents issued and pending on the breath test employed in this study. None of the other authors has any conflict of interest or financial interest with regard to this article.Supported by a grant from the NHLBI (2R44HL59715).

PII: S1053-2498(03)00354-1

doi:10.1016/j.healun.2003.07.017

The Journal of Heart and Lung Transplantation
Volume 23, Issue 6 , Pages 701-708, June 2004

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