Key result
Prior MI in pigs reduces baseline LV regional function ~45% and alters MT1-MMP activity during ischemia-reperfusion.
RCT (n=30)
Randomized
Absolute Event Rate: 103% vs 188%
p-value: p=<0.05
A previous myocardial infarction alters the regional MT1-MMP response to subsequent ischemia-reperfusion, which may contribute to continued adverse remodeling and regional dysfunction.
MT1-MMP may worsen post-MI LV function after I/R; leaves open whether targeting it preserves regional performance.
After a myocardial infarction (MI), an episode of ischemia-reperfusion (I/R) can result in a greater impairment of left ventricular (LV) regional function (LVRF) than that caused by an initial I/R episode in the absence of MI. Membrane type-I matrix metalloproteinase (MT1-MMP) proteolytically processes the myocardial matrix and is upregulated in LV failure. This study tested the central hypothesis that a differential induction of MT1-MMP occurs and is related to LVRF after I/R in the context of a previous MI. Pigs with a previous MI [3 wk postligation of the left circumflex artery (LCx)] or no MI were randomized to undergo I/R [60-min/120-min left anterior descending coronary artery (LAD) occlusion] or no I/R as follows: no MI and no I/R (n = 6), no MI and I/R (n = 8), MI and no I/R (n = 8), and MI and I/R (n = 8). Baseline LVRF (regional stroke work, sonomicrometry) was lower in the LAD region in the MI group compared with no MI (103 ± 12 vs. 188 ± 26 mmHg·mm, P < 0.05) and remained lower with peak ischemia (35 ± 8 vs. 88 ± 17 mmHg·mm, P < 0.05). Using a novel interstitial microdialysis method, MT1-MMP was directly measured and was over threefold higher in the LCx region and over twofold higher in the LAD region in the MI group compared with the no MI group at baseline. MT1-MMP fluorogenic activity was persistently elevated in the LCx region in the MI and I/R group but remained unchanged in the LAD region. In contrast, no changes in MT1-MMP occurred in the LCx region in the no MI and I/R group but increased in the LAD region. MT1-MMP mRNA was increased by over threefold in the MI region in the MI and I/R group. In conclusion, these findings demonstrate that a heterogeneous response in MT1-MMP activity likely contributes to regional dysfunction with I/R and that a subsequent episode of I/R activates a proteolytic cascade within the MI region that may contribute to a continued adverse remodeling process.
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Dixon et al. (2010) conducted an RCT in Myocardial infarction and ischemia-reperfusion (n=30). Ischemia-reperfusion (60-min/120-min LAD occlusion) vs. No ischemia-reperfusion was evaluated on Baseline left ventricular regional function (regional stroke work) in the LAD region (p=<0.05). Previous myocardial infarction in pigs resulted in lower baseline left ventricular regional function compared to no MI (103 vs 188 mmHg·mm, P<0.05) and altered MT1-MMP activity during ischemia-reperfusion.
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