Expression of extracellular matrix genes during myocardial recovery from heart failure after left ventricular assist device support.
BACKGROUND
Abnormalities in the extracellular matrix (ECM) can occur in heart failure. In this study we analyzed ECM gene expression in patients with advanced dilated cardiomyopathy who did and did not develop sustained myocardial recovery after left ventricular assist device (LVAD) unloading combined with pharmacologic therapy.


METHODS
Myocardial gene expression of collagens (COL1A1 and COL3A1), fibronectin (FN), matrix metalloproteinases (MMPs 1 to 14), tissue inhibitors of metalloproteinases (TIMPs 1 to 4), connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-beta1) and THY1 was measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) at LVAD implantation and again at explantation (recovery, n = 11) or transplantation (non-recovery, n = 5).


RESULTS
The non-recovery group had higher levels of pro-fibrotic markers (COL1A1, TGF-beta1 and THY1) at implantation compared with the recovery group (1.82 +/- 0.74-, 1.81 +/- 0.69- and 3.01 +/- 1.70-fold, respectively; p <or= 0.05). Both recovery and non-recovery groups showed no significant difference in gene expression after treatment, but levels of pro-fibrotic genes (COL1A1, COL3A1, FN and THY1) correlated negatively with post-explant ejection fraction in the recovery group. Of all genes analyzed only TIMP4 showed a significant change, with expression reduced during recovery (0.55 +/- 0.25-fold at explant vs implant, p = 0.001). All other genes showed complex patterns between individuals with both increased and decreased expression of pro-fibrotic markers, MMPs and TIMPs in recovery patients.


CONCLUSIONS
Patients who did not recover had higher myocardial expression of pro-fibrotic genes at LVAD implantation, and in recovered patients higher levels at explant were negatively associated with subsequent ejection fraction. However, individual patients showed complex expression patterns and a decrease in pro-fibrotic markers was not required for recovery.
Felkin
Leanne E
LE
Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College London, Harefield, Middlesex, UK.
Lara-Pezzi
Enrique
E
George
Robert
R
Yacoub
Magdi H
MH
Birks
Emma J
EJ
Barton
Paul J R
PJ
D003094:Collagen / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000235:genetics / Q000601:surgery*; D006353:Heart-Assist Devices; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018800:Thy-1 Antigens / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D017211:Treatment Failure; D016896:Treatment Outcome
C499252:COL23A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D018800:Thy-1 Antigens; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003094:Collagen; D020782:Matrix Metalloproteinases