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Foreword by Professor Sir Magdi Yacoub | |
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Alterations in gene expression in heart failure and recovery A major focus of our research is to establish a gene expression profile of myocardial recovery from heart failure following left ventricular assist (LVAD) support and pharmacological treatment including clenbuterol in patients following the Harefield Protocol. We have made extensive use of quantitative real time PCR (TaqMan) to analyse specific gene families in myocardial samples taken at the time of LVAD implantation and biopsies following recovery (taken at the time of device removal) and at one year follow up. The study is unique in that it specifically addresses recovery whereas all previous studies have focussed on LVAD as a bridge to transplantation without recovery. Using protocols we specifically developed for small (mm 3 ) myocardial samples and without the need for RNA amplification, we have defined the pattern of expression of several key gene families including the matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), cytokines, Toll-like receptors, natriuretic factors, stem cell factors and insulin-like growth factor (IGF-I). The study has provided unique insight into the molecular changes associated with myocardial recovery. We are particularly interested that myocardial IGF-I is elevated in recovery patients at explant given the beneficial potential of this growth factor on the myocardium, and our in vitro data which show that myocytes up-regulate IGF-I in response to clenbuterol. Our data also reveal an intriguing correlation between IGF-I levels and the stem cell factor SDF-1 raising the possibility that IGF-I expression may be linked to stem cell recruitment. Current research is focussed on expanding this study using micro-array analysis in collaboration with Dr Jennifer Hall, Cardiovascular Genomics, Lillehei Heart Institute Minneapolis, USA. back to Molecular Biology main page
Further Reading Barton PJR, Felkin LE, Birks EJ, Cullen ME, Banner NR, Grindle S, Hall JL, Miller LW, & Yacoub MH. Role of myocardial IGF-I gene expression during recovery from heart failure following combined LVAD and clenbuterol therapy. Circulation (in press). Felkin LE, Taegtmeyer AB, & Barton PJR. Real-Time Quantitative PCR in Cardiac Transplant Research. In “Transplantation Immunology”, eds. Hornick P & Rose, M. L. Methods in Molecular Biology , Humana Press, Inc. in press. Barton PJR, Birks EJ, Felkin LE, Cullen ME, Koban MU, & Yacoub MH (2003). Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure. The Journal of Heart & Lung Transplantation 22 , 738-744.
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