A quantitative gene expression profile of matrix metalloproteinases (MMPS) and their inhibitors (TIMPS) in the myocardium of patients with deteriorating heart failure requiring left ventricular assist device support.
BACKGROUND
Mechanisms underlying the rapid deterioration of heart failure patients who subsequently require left ventricular assist device (LVAD) support are poorly understood. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a key role in myocardial remodelling and heart failure. We hypothesized that MMP and TIMP expression would be altered in these patients.


METHODS
Quantitative polymerase chain reaction was used to measure myocardial messenger RNA levels of MMP1 to MMP14, TIMP1 to TIMP4, collagen I and collagen III in 24 dilated cardiomyopathy (DCM) patients with deteriorating clinical status who required LVAD support (LVAD Group) and in 7 stable DCM patients undergoing transplantation without need for LVAD support (Tx Group).


RESULTS
Levels of MMP1, MMP8 and TIMP4 were higher in the LVAD Group compared with the Tx Group (188% +/- 141%, 646% +/- 432%, and 66% +/- 33% higher, respectively, p < 0.05) whereas MMP2, MMP9, MMP10, MMP11, and MMP14 levels were similar. MMP3, MMP7, MMP12, and MMP13 were undetectable. All TIMPs were generally higher in the LVAD group, but only TIMP4 reached significance. Collagen I and III were not altered. We tested for correlations between MMP and TIMP expression with myocardial cytokine levels. MMP8 correlated positively with interleukin-6 and interleukin-1beta, suggesting a link between cytokines and MMPs in these patients.


CONCLUSIONS
The data show that high myocardial collagenase (MMP1 and MMP8) expression without compensatory changes in collagen or TIMP expression is a feature of patients requiring LVAD support. This may be linked in part to elevated cytokine expression and suggests collagenase activity may be an important therapeutic target in deteriorating heart failure.
Felkin
Leanne E
LE
National Heart and Lung Institute, Imperial College London, Heart Science Centre, Harefield, Middlesex.
Birks
Emma J
EJ
George
Robert
R
Wong
Sissie
S
Khaghani
Asghar
A
Yacoub
Magdi H
MH
Barton
Paul J R
PJ
D000293:Adolescent; D000328:Adult; D002303:Cardiac Output, Low / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002648:Child; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006352:Heart Ventricles; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D012720:Severity of Illness Index; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D020781:Matrix Metalloproteinase 1; D020784:Matrix Metalloproteinase 8; D020782:Matrix Metalloproteinases; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C488762:MMP8 protein, human