Prognostic Value of Tissue Inhibitor of Metalloproteinase-Matrix Metalloproteinase Biomarkers at 30 Days in Patients with Acute Myocardial Infarction Without Reperfusion Therapy
Ischemic coronary artery disease remains the leading cause of heart failure (HF), a significant public health burden globally. Over the past decades, advancements in pharmacological therapies and early reperfusion strategies have substantially reduced mortality associated with acute myocardial infarction (AMI). However, the improved survival rates have also expanded the pool of patients susceptible to cardiac remodeling and adverse cardiovascular (CV) outcomes. Cardiac remodeling, a critical process following AMI, involves extracellular matrix proteolysis and turnover. The tissue inhibitor of metalloproteinase-matrix metalloproteinase (TIMP-MMP) axis has been implicated in these structural and functional changes, making it a potential area of interest for prognostic biomarkers.
This study aimed to systematically analyze the association between post-AMI CV outcomes at 30 days and TIMP-MMP family biomarkers, assessing their potential prognostic value. The study included 1105 AMI patients from the China Patient-centered Evaluative Assessment of Cardiac Events (China PEACE) prospective AMI study. The inclusion criteria were: (1) no prior AMI, (2) no reperfusion treatment (thrombolysis, percutaneous coronary intervention, or coronary artery bypass grafting) during the index AMI hospitalization, and (3) blood samples collected within 72 hours of symptom onset. The study was approved by the Ethics Committee at Fuwai Hospital and registered at clinicaltrials.gov.
Clinical outcomes were defined as hospitalized HF and CV-related events. Hospitalized HF was characterized by admission for new or worsening HF symptoms. CV-related events were a composite of non-fatal CV events (AMI, revascularization, angina pectoris, ischemic stroke, HF) and CV death, excluding elective revascularization. Blood samples were collected within the first 24 hours of hospital admission. N-terminal pro b-type natriuretic peptide (NT-proBNP) was measured using a Cobas e601 analyzer. TIMP3 was tested using an Abnova enzyme-linked immunosorbent assay kit, while MMP2, MMP8, MMP9, TIMP1, TIMP2, and TIMP4 were assessed using Bio-Plex Pro Human MMP and TIMP panel kits.
Within the 30-day follow-up, 20 (1.80%) patients developed HF, and 64 (5.79%) patients experienced CV-related events. Kaplan-Meier plots were used to determine cut-off points for biomarker concentrations based on receiver operating characteristic curve analysis. For HF events, patients with NT-proBNP (cut-off: 2724 pg/mL), TIMP1 (cut-off: 213 ng/mL), or TIMP4 (cut-off: 2.75 ng/mL) concentrations above the cut-off had higher event rates. Similarly, for CV-related events, patients with NT-proBNP (cut-off: 1953 pg/mL), TIMP1 (cut-off: 192 ng/mL), TIMP2 (cut-off: 118 ng/mL), or TIMP4 (cut-off: 2.83 ng/mL) concentrations above the cut-off had higher event rates.
Cox regression models, adjusted for age and sex, revealed that NT-proBNP, TIMP1, and MMP2/TIMP1 ratio at baseline were significantly associated with both HF and CV-related events during the 30-day follow-up. The MMP8/TIMP1 ratio was only associated with CV-related events. The prognostic value of the biomarkers was further evaluated using c-statistics. For HF events, combining NT-proBNP with TIMP4, MMP2/TIMP1, TIMP1, or MMP2/TIMP4 improved the c-statistics values compared to NT-proBNP alone. However, for CV events, none of the c-statistics values reached 0.7 when combining NT-proBNP with any TIMP-MMP biomarker.
The study found that baseline TIMP1 levels were associated with HF and CV-related events post-AMI, consistent with previous research. A large population-based study linked elevated TIMP1 levels with increased risk of CV events, coronary artery disease, AMI, stroke, and all-cause death over a 13-year follow-up. Another study reported that elevated TIMP1 levels were associated with a higher chance of major adverse cardiovascular events in AMI patients. The prognostic value of TIMP1 for HF was further supported by the c-statistics model, indicating its clinical utility as a biomarker in HF outcomes for AMI patients without reperfusion treatment.
While elevated MMP2 levels have been associated with clinical outcomes such as infarct size and left ventricular dysfunction in MI patients, this study found no association between baseline MMP2 levels and the risk of HF or CV-related events within 30 days post-AMI in patients without reperfusion treatment. This discrepancy may be due to the different outcomes observed or the short follow-up period. However, the MMP2/TIMP1 ratio showed predictive value for a decreased risk of HF and CV-related events, suggesting that the imbalance between MMP2 and TIMP1 post-AMI could predict these outcomes.
Previous research has linked elevated MMP8 levels and MMP8/TIMP1 ratio with the risk of MI over a 13-year follow-up. In this study, the MMP8/TIMP1 ratio, but not MMP8 level, independently predicted CV-related events, potentially due to the short 30-day follow-up period. MMP8 is known to participate in late remodeling events, which may not be captured within this timeframe.
In conclusion, this study demonstrated that MMPs and TIMPs at the acute stage could predict the occurrence of HF or CV-related events within 30 days in AMI patients without reperfusion therapy. Specifically, TIMP1 levels and the MMP2/TIMP1 ratio in plasma were predictive of HF and CV-related events, while the MMP8/TIMP1 ratio predicted CV-related events. Combining biomarkers such as TIMP4, MMP2/TIMP1, or TIMP1 with NT-proBNP provided incremental prognostic value in the c-statistics model. Further studies are warranted to evaluate the potential of these biomarkers for prognosis and early intervention in AMI patients.
doi.org/10.1097/CM9.0000000000001144
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