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MMP-9 and its regulators TIMP-1 and EMMPRIN in acute ST-elevation myocardial infarction.
A sub-study of the NORDISTEMI trial.
Opstad TB 1,3,4, Halvorsen S 2,3,4, Arnesen H 1,3,4, Seljeflot I 1,2,3,4
1 Center
for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway
2 Department
3
of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway,
Center for Heart Failure Research, Oslo University Hospital, Norway
4 Faculty
of Medicine, University of Oslo, Norway
Background
Elevation of matrix metalloproteinase (MMP)-9 is associated with plaque rupture and acute myocardial
infarction (AMI). As the extracellular matrix (ECM) is involved in wound repair, we aimed to investigate
whether levels of MMP-9, its inhibitor TIMP-1 and the inducer EMMPRIN are associated with infarct size,
left ventricular function and future clinical events in patients with AMI.
Materials and Methods
This was a sub-study (n=243) of the NORDISTEMI trial, in which AMI-patients were randomized to
thrombolysis followed by early or late invasive strategy. Circulating MMP-9, TIMP-1 and EMMPRIN were
measured at Day 3 and 3 months. Infarct size and left ventricular ejection fraction (LVEF) assessed by
SPECT (n=230) and MRI (n=160) were measured at 3 months.
Results
Levels of MMP-9, TIMP-1, EMMPRIN and the MMP-9/TIMP-1 ratio declined from Day 3 to 3 months
(p<0.001, all), with similar relative changes in both treatment groups. Day 3 levels of TIMP-1 correlated
significantly to infarct size assessed by SPECT and MRI at 3 months, and to peak Troponin T (p<0.04, all)
and NT-pro BNP levels at 3 days (p<0.001). There was no significant correlation to LVEF, measured by
MRI (p=0.08).
Clinical endpoint (death, AMI, stroke) after 1 year was recorded in 24 patients, in whom MMP-9 levels and
the MMP-9/TIMP-1 ratio were significantly elevated at both time-points (p≤0.02, all). MMP-9 levels at Day
3 and 3 months were associated with a 3- and 6-fold increased risk of events, respectively, (adjusted
p≤0.01, both).
Conclusion
MMP-9 and its regulators were all reduced at 3 months after AMI compared to acute phase levels. The
significant association between Day 3 levels of TIMP-1 and infarct size and NT-proBNP indicate a role of
TIMP-1 in the ECM remodeling process, beyond MMP-9 inhibition. MMP-9 levels in the subacute phase
associated with 1-year clinical outcomes, in accordance with previous reports.