Usefulness of plasma tissue inhibitors of metalloproteinases as markers of prognosis after acute myocardial infarction.

Alterations in the balance of matrix metalloproteinase to tissue inhibitor of metalloproteinase (TIMP) are seen after acute myocardial infarction (AMI) and are associated with adverse left ventricular remodeling and prognosis in this setting. We aimed to investigate the association between TIMP levels and the occurrence of major adverse cardiac events (MACEs) after AMI. We measured plasma TIMP-1, -2, and -4 levels in 1,313 patients presenting with AMI. Subjects were followed over a median period of 520 days for the occurrence of MACEs. Clinical risk was assessed using the Global Registry of Acute Coronary Events (GRACE) score. All TIMP levels correlated with patient age and inversely with estimated glomerular filtration rate (all p values <0.001). Levels were higher in women versus men (p <0.001) and in subjects with a history of diabetes (TIMP-1, p <0.001; TIMP-2, p = 0.002; TIMP-4, p <0.001) or hypertension (TIMP-1, p = 0.031; TIMP-2, p <0.001; TIMP-4, p <0.001). TIMP-1 and TIMP-4 were higher in subjects with previous MI or angina (p <0.001). TIMP levels increased incrementally with quartiles of GRACE score (p <0.001). All TIMPs showed univariate association with the occurrence of MACEs (p <0.001). Areas under the receiver operator characteristic curve for prediction of MACE at 1 year were 0.61 for TIMP-1, 0.57 for TIMP-2, and 0.64 for TIMP-4. Combination of TIMPs with GRACE risk score revealed a greater area under the curve than GRACE score alone (0.72 vs 0.69, p = 0.0015). On multivariable Cox proportional hazards analysis, GRACE score (p <0.001) and plasma TIMPs (log TIMP-1, p = 0.017; log TIMP-2, p <0.001; log TIMP-4, p = 0.011) independently predicted MACEs. Using Kaplan-Meier analysis, the risk of MACEs increased incrementally with the number of TIMPs above their respective median (p <0.001 for all comparisons, log-rank test). In conclusion, higher plasma TIMP-1, -2, and -4 after AMI are associated with MACEs and provide additional prognostic information to that obtained from GRACE clinical risk scores alone.