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(Circulation. 2006;114:I-21 – I-26.)
© 2006 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Congestive Heart Failure

Gene Expression Profiles and B-Type Natriuretic Peptide Elevation in Heart Transplantation

More Than a Hemodynamic Marker

Mandeep R. Mehra, MD; Patricia A. Uber, Pharm D; Dirk Walther, PhD; Mark Vesely, MD; Jay G. Wohlgemuth, MD; James Prentice, MS; Darren Tayama, MD; Margaret Billingham, MD

From University of Maryland School of Medicine (M.R.M., P.A.U., M.V.), Baltimore, Md; XDx Inc (D.W., J.G.W., J.P., D.T.), South San Francisco, Calif; Stanford University (M.B.), Stanford, Calif.

Correspondence to Mandeep R. Mehra, Herbert Berger Professor and Head of Cardiology, University of Maryland Medical Center, 22 South Greene Street–S3B06, Baltimore, MD 21201. E-mail: mmehra{at}medicine.umaryland.edu

Background— B-type natriuretic peptide (BNP) is chronically elevated in heart transplantation and reflects diastolic dysfunction, cardiac allograft vasculopathy, and poor late outcome. This investigation studied peripheral gene expression signatures of elevated BNP concentrations in clinically quiescent heart transplant recipients in an effort to elucidate molecular correlates beyond hemodynamic perturbations.

Methods and Results— We performed gene microarray analysis in peripheral blood mononuclear cells of 28 heart transplant recipients with clinical quiescence (absence of dyspnea or fatigue; normal left ventricular ejection fraction [EF >55%]; ISHLT biopsy score 0 or 1A; and normal hemodynamics [RAP <7 mm Hg, PCWP 15 mm Hg, and CI 2.5 L/min per m²]). BNP levels were performed using the Triage B-type Natriuretic Peptide test (Biosite Diagnostics Inc, San Diego, Calif) and median BNP concentration was 165 pg/mL. Seventy-eight probes (of 7370) mapped to 54 unique genes were significantly correlated with BNP concentrations (P<0.001). Of these, the strongest correlated genes (P<0.0001) were in the domains of gelsolin (actin cytoskeleton), matrix metallopeptidases (collagen degradation), platelet function, and immune activity (human leukocyte antigen system, heat shock protein, mast cell, and B-cell lineage).

Conclusions— In the clinically quiescent heart transplant recipient, an elevated BNP concentration is associated with molecular patterns that point to ongoing active cardiac structural remodeling, vascular injury, inflammation, and alloimmune processes. Thus, these findings allude to the notion that BNP elevation is not merely a hemodynamic marker but should be considered reflective of integrated processes that determine the balance between active cardiac allograft injury and repair.

Key Words: gene expression • heart transplantation • natriuretic peptides