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European Heart Journal Advance Access published online on November 28, 2006
European Heart Journal, doi:10.1093/eurheartj/ehl365
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Molecular signature of recovery following combination left ventricular assist device (LVAD) support and pharmacologic therapy

Jennifer L. Hall1,*, Emma J. Birks2,3, Suzanne Grindle1, Martin E. Cullen2, Paul J. Barton2, James E. Rider1, Sangjin Lee1, Subash Harwalker1, Ami Mariash1, Neeta Adhikari1, Nathan J. Charles1, Leanne E. Felkin2, Sean Polster1, Leslie W. Miller1 and Magdi H. Yacoub2

1 Lillehei Heart Institute, Division of Cardiology, Department of Medicine, University of Minnesota, Mayo Mail Code 508, 420 Delaware Street SE, Minneapolis, MN 55455, USA
2 Heart Science Centre, National Heart and Lung Institute, Imperial College, Harefield, Middlesex, UK
3 Transplant Unit, Royal Brompton and Harefield NHS Trust, Harefield, Middlesex, UK

Received 9 July 2006; revised 29 September 2006; accepted 20 October 2006.

* Corresponding author. Tel: +1 612 626 4566; fax: +1 612 626 4411. E-mail address: jlhall{at}umn.edu

Aims A novel combination therapy consisting of a left ventricular assist device (LVAD) combined with pharmacologic therapy including the selective ß2-agonist, clenbuterol, has shown promise in restoring ventricular function in patients with heart failure. The aim of this study was to identify common genes and signalling pathways whose expression was associated with reversal of heart failure and restoration of ventricular function.

Methods and results Microarray analysis was performed on six paired human heart samples harvested at the time of LVAD implant and at the time of LVAD explant for recovery of ventricular function (post). Follow-up data shows that the improvements in ventricular function have been maintained for an average of 3.8 years post-explant. Analysis of the gene expression data revealed: (i) a significant association of integrin pathway signalling with recovery and (ii) the identification of several novel targets including, EPAC2, in the well-described cAMP pathway whose expression was down-regulated with recovery, and was associated with improvements in cardiac contractility, metabolism, and function.

Conclusion This data set represents the first description of signalling pathways associated with the functional recovery of end-stage human heart failure and the identification of new targets in the human heart that are modified by this combination therapy.

Key Words: Heart failure • Left ventricular assist device • EPAC2 • Genomics • Gene expression


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