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Usefulness of Matrix Metalloproteinase-9 Plasma Levels to Identify Patients With Preserved Left Ventricular Systolic Function After Acute Myocardial Infarction Who Could Benefit from Eplerenone

      We sought to assess possible interactions between eplerenone use and a plasma marker of collagen turnover on prognosis in patients after acute myocardial infarction (AMI) and preserved left ventricular (LV) ejection fraction (≥40%). Three hundred three patients with AMI (58 ± 11 years old, 249 men) and preserved systolic LV function were studied prospectively for 24 months. Plasma levels of matrix metalloproteinase-9 (MMP-9) were assessed on day 7 after AMI. Patients were categorized according to whether (n = 201) or not (n = 102) they received eplerenone (25 mg/day) and their baseline MMP-9 levels using the cut-off level suggested by receiver operating characteristics analysis (12.7 ng/ml). Death from cardiovascular causes, nonfatal reinfarction, hospitalization for unstable angina, and development of heart failure symptoms were considered study end points. Eplerenone use was not associated with better prognosis in the entire study group (p = 0.132). However, a significant beneficial eplerenone effect on outcome was observed in patients with low baseline levels of MMP-9 (event-free survival for eplerenone vs noneplerenone arm 65% vs 35%, p = 0.005). Eplerenone had no effect (p = 0.741) in the subgroup of patients with high baseline MMP-9 levels. In conclusion, in patients after AMI with preserved LV systolic function, low baseline levels of MMP-9 identify a subgroup of patients in whom eplerenone use is associated with a survival benefit.
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      References

        • Van de Werf F.
        • Bax J.
        • Betriu A.
        • Blomstrom-Lundqvist C.
        • Crea F.
        • Falk V.
        • Filippatos G.
        • Fox K.
        • Huber K.
        • Kastrati A.
        • Rosengren A.
        • Steg P.G.
        • Tubaro M.
        • Verheugt F.
        • Weidinger F.
        • Weis M.
        • ESC Committee for Practice Guidelines (CPG)
        Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology.
        Eur Heart J. 2008; 29: 2909-2945
        • Zamilpa R.
        • Lindsey M.L.
        Extracellular matrix turnover and signaling during cardiac remodeling following MI: causes and consequences.
        J Mol Cell Cardiol. 2010; 48: 558-563
        • Spinale F.G.
        Matrix metalloproteinases: regulation and dysregulation in the failing heart.
        Circ Res. 2002; 90: 520-530
        • Mukherjee R.
        • Mingoia J.T.
        • Bruce J.A.
        • Austin J.S.
        • Stroud R.E.
        • Escobar G.P.
        • McClister Jr, D.M.
        • Allen C.M.
        • Alfonso-Jaume M.A.
        • Fini M.E.
        • Lovett D.H.
        • Spinale F.G.
        Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction.
        Am J Physiol Heart Circ Physiol. 2006; 291: H2216-H2228
        • Tao Z.Y.
        • Cavasin M.A.
        • Yang F.
        • Liu Y.H.
        • Yang X.P.
        Temporal changes in matrix metalloproteinase expression and inflammatory response associated with cardiac rupture after myocardial infarction in mice.
        Life Sci. 2004; 74: 1561-1572
        • Peterson J.T.
        • Li H.
        • Dillon L.
        • Bryant J.W.
        Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat.
        Cardiovasc Res. 2000; 46: 307-315
        • Wilson E.M.
        • Moainie S.L.
        • Baskin J.M.
        • Lowry A.S.
        • Deschamps A.M.
        • Mukherjee R.
        • Guy T.S.
        • St John-Sutton M.G.
        • Gorman III, J.H.
        • Edmunds Jr, L.H.
        • Gorman R.C.
        • Spinale F.G.
        Region- and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling.
        Circulation. 2003; 107: 2857-2863
        • Orn S.
        • Manhenke C.
        • Squire I.B.
        • Ng L.
        • Anand I.
        • Dickstein K.
        Plasma MMP-2, MMP-9 and N-BNP in long-term survivors following complicated myocardial infarction: relation to cardiac magnetic resonance imaging measures of left ventricular structure and function.
        J Card Fail. 2007; 13: 843-849
        • Kelly D.
        • Cockerill G.
        • Ng L.L.
        • Thompson M.
        • Khan S.
        • Samani N.J.
        • Squire I.B.
        Plasma matrix metalloproteinase-9 and left ventricular remodelling after acute myocardial infarction in man: a prospective cohort study.
        Eur Heart J. 2007; 28: 711-718
        • Squire I.B.
        • Evans J.
        • Ng L.L.
        • Loftus I.M.
        • Thompson M.M.
        Plasma MMP-9 and MMP-2 following acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of left ventricular dysfunction.
        J Card Fail. 2004; 10: 328-333
        • Wagner D.R.
        • Delagardelle C.
        • Ernens I.
        • Rouy D.
        • Vaillant M.
        • Beissel J.
        Matrix metalloproteinase-9 is a marker of heart failure after acute myocardial infarction.
        J Card Fail. 2006; 12: 66-72
        • Matsunaga T.
        • Abe N.
        • Kameda K.
        • Hagii J.
        • Fujita N.
        • Onodera H.
        • Kamata T.
        • Ishizaka H.
        • Hanada H.
        • Osanai T.
        • Okumura K.
        Circulating level of gelatinase activity predicts ventricular remodeling in patients with acute myocardial infarction.
        Int J Cardiol. 2005; 105: 203-208
        • Kelly D.
        • Khan S.Q.
        • Thompson M.
        • Cockerill G.
        • Ng L.L.
        • Samani N.
        • Squire I.B.
        Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction.
        Eur Heart J. 2008; 29: 2116-2124
        • Bril A.
        • Percevault-Albadini J.
        • Landais J.
        • Toseland C.
        • Gout B.
        Ventricular remodelling and tolerance to ischaemia in rabbits with myocardial infarction.
        J Mol Cell Cardiol. 1994; 26: 322-330
        • Yarbrough W.M.
        • Mukherjee R.
        • Escobar G.P.
        • Mingoia J.T.
        • Sample J.A.
        • Hendrick J.W.
        • Dowdy K.B.
        • McLean J.E.
        • Lowry A.S.
        • O'Neill T.P.
        • Spinale F.G.
        Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling.
        Circulation. 2003; 108: 1753-1759
        • Jugdutt B.I.
        Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough?.
        Circulation. 2003; 108: 1395-1403
        • Vanhoutte D.
        • Schellings M.
        • Pinto Y.
        • Heymans S.
        Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: a temporal and spatial window.
        Cardiovasc Res. 2006; 69: 604-613
        • Sun Y.
        Myocardial repair/remodelling following infarction: roles of local factors.
        Cardiovasc Res. 2009; 81: 482-490
        • Zannad F.
        • Radauceanu A.
        Effect of MR blockade on collagen formation and cardiovascular disease with a specific emphasis on heart failure.
        Heart Fail Rev. 2005; 10: 71-78
        • Rudolph A.E.
        • Rocha R.
        • McMahon E.G.
        Aldosterone target organ protection by eplerenone.
        Mol Cell Endocrinol. 2004; 217: 229-238
        • Wang D.
        • Liu Y.H.
        • Yang X.P.
        • Rhaleb N.E.
        • Xu J.
        • Peterson E.
        • Rudolph A.E.
        • Carretero O.A.
        Role of a selective aldosterone blocker in mice with chronic heart failure.
        J Card Fail. 2004; 10: 67-73
        • Iraqi W.
        • Rossignol P.
        • Angioi M.
        • Fay R.
        • Nuée J.
        • Ketelslegers J.M.
        • Vincent J.
        • Pitt B.
        • Zannad F.
        Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study.
        Circulation. 2009; 119: 2471-2479
        • Zannad F.
        • Alla F.
        • Dousset B.
        • Perez A.
        • Pitt B.
        Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES).
        Circulation. 2000; 102: 2700-2706
        • Weir R.A.
        • Mark P.B.
        • Petrie C.J.
        • Clements S.
        • Steedman T.
        • Ford I.
        • Ng L.L.
        • Squire I.B.
        • Wagner G.S.
        • McMurray J.J.
        • Dargie H.J.
        Left ventricular remodeling after acute myocardial infarction: does eplerenone have an effect?.
        Am Heart J. 2009; 157: 1088-1096
        • Adamopoulos C.
        • Ahmed A.
        • Fay R.
        • Angioi M.
        • Filippatos G.
        • Vincent J.
        • Pitt B.
        • Zannad F.
        • EPHESUS Investigators
        Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial.
        Eur J Heart Fail. 2009; 11: 1099-1105