Myocardial insulin-like growth factor-I gene expression during recovery from heart failure after combined left ventricular assist device and clenbuterol therapy.
BACKGROUND
Patients who undergo mechanical support with a left ventricular assist device (LVAD) exhibit reverse remodeling and in some cases recover from heart failure. We have developed a combination therapy using LVAD support combined with pharmacological therapy to maximize reverse remodeling, followed by the beta2 adrenergic agonist clenbuterol. We recently found that clenbuterol induces insulin-like growth factor I (IGF-I) in cardiac myocytes in vitro. The purpose of this study is to examine IGF-I expression in recovery patients after combination therapy.


RESULTS
Myocardial mRNA levels were determined by real-time quantitative polymerase chain reaction in 12 recovery patients (at LVAD implantation, explantation, and 1 year after explantation). IGF-I mRNA was elevated at the time of LVAD explantation relative to donors, with 2 groups distinguishable: Those with low IGF-I mRNA at implantation who showed significant increase during recovery and those with high IGF-I mRNA at implantation who remained high. Levels returned to normal by 1 year after explantation. Microarray analysis of implantation and explantation samples of recovery patients further revealed elevated IGF-II and IGF binding proteins IGFBP4 and IGFBP6. IGF-I levels correlated with stromal cell-derived factor mRNA measured both in LVAD patients and in a wider cohort of heart failure patients.


CONCLUSIONS
The data suggest involvement of elevated myocardial IGF-I mRNA in recovery. IGF-I may act to limit atrophy and apoptosis during reverse remodeling and to promote repair and regeneration in concert with stromal cell derived factor.
Barton
Paul J R
PJ
National Heart and Lung Institute, Imperial College London, Heart Science Centre, London, UK. p.barton@imperial.ac.uk
Felkin
Leanne E
LE
Birks
Emma J
EJ
Cullen
Martin E
ME
Banner
Nicholas R
NR
Grindle
Suzanne
S
Hall
Jennifer L
JL
Miller
Leslie W
LW
Yacoub
Magdi H
MH
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000601:surgery; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D002976:Clenbuterol / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003289:Convalescence; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D006353:Heart-Assist Devices; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000096:biosynthesis / Q000235:genetics; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000096:biosynthesis / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume; D020257:Ventricular Remodeling / Q000235:genetics
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D018974:Insulin-Like Growth Factor Binding Protein 4; D018976:Insulin-Like Growth Factor Binding Protein 6; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D002976:Clenbuterol