Comparison of matrix metalloproteinase 9 and brain
natriuretic peptide as clinical biomarkers in chronic
Esther E. Vorovich, MD,aShaokun Chuai, MS,bMingyao Li, PhD,bJustin Averna, BS,aVictor Marwin, BA,a
David Wolfe, RN,aMuredach P. Reilly, MB, MSCE,aand Thomas P. Cappola, MD, ScMaPhiladelphia, PA
Background Matrix metalloproteinase 9 (MMP-9) may serve as a biomarker of ventricular remodeling in selected
populations, but few studies have assessed its performance in clinical practice. We tested MMP-9 as a biomarker of
remodeling and predictor of outcomes in a systolic heart failure cohort derived from clinical practice and compared its
performance to brain natriuretic peptide (BNP).
Methods Plasma MMP-9 and BNP levels were measured in 395 outpatients with systolic heart failure who participated in
the Penn Heart Failure Study. We tested for (1) cross-sectional associations between biomarker levels, left ventricular end-
diastolic dimension index (LVEDDI), and ejection fraction (EF), and (2) associations between baseline biomarker levels and risk
of subsequent cardiac hospitalization or death over 3 years of follow-up.
Results Matrix metalloproteinase 9 had no significant correlation with LVEDDI (ρ = 0.04, P = not significant) or EF
(ρ = −0.06, P = not significant), whereas BNP showed highly significant correlations (LVEDDI: ρ = −0.27, P b .0001; EF:
.6) or EF (P = .14), whereas BNP showed strong independent associations (LVEDDI: P b .001; EF: P = .002). Kaplan-Meier
analyses showed no difference in hospital-free survival by baseline MMP-9 tertile (P = .7), whereas higher BNP tertile predicted
Conclusion Compared to BNP, MMP-9 is a poor clinical biomarker of remodeling and outcome in patients with systolic
heart failure derived from clinical practice. (Am Heart J 2008;0:1-6.)
In response to pathologic stress, the failing left ventricle
undergoes a complex process of remodeling that is
characterized at the cellular level by cardiac myocyte
hypertrophy and interstitial fibrosis.1Research in animal
models has shown that increased expression of brain
natriuretic peptide (BNP) is a hallmark of myocyte
hypertrophy,2and subsequent work in human subjects
has established circulating BNP as an important biomar-
ker in the clinical management of acute and chronic heart
failure.3By contrast, there is no clinically used biomarker
of interstitial fibrosis, although it is a cardinal feature of
virtually all forms of heart failure.
Fibrosis is a complex process that is mediated to a large
extent by matrix metalloproteinases (MMPs) and endo-
genous tissue inhibitors of matrix metalloproteinases
(TIMPs).4,5Accordingly, circulating levels of MMPs and
TIMPs have been proposed as potential biomarkers of
ventricular remodeling and heart failure. Among the
many MMPs and TIMPs, MMP-9 has shown promising
associations with echocardiographic parameters in
population-based cohorts6and in substudies of clinical
trials.7However, there are limited data assessing the
performance of MMP-9 as a biomarker in clinical cohorts
more representative of patients encountered in clinical
practice.8,9Moreover, no study has compared the
performance of MMP-9 with BNP in patients with chronic
heart failure, although BNP is in widespread clinical use.
The purpose of this study was to compare the
performance of MMP-9 and BNP as biomarkers of cardiac
remodeling and outcome in a clinical cohort of patients
From theaPenn Cardiovascular Institute, University of Pennsylvania School of Medicine,
Philadelphia, PA, andbDepartment of Biostatistics and Epidemiology, Center for Clinical
Epidemiology and Biostatistics, University of Pennsylvania School of Medicine,
This study was supported by research grants from the National Institutes of Health (NIH
K23HL071562 and R01HL088577) and Abbott Diagnostics. Assays were performed in
collaboration with the University of Pennsylvania Diabetes and Endocrinology Research
Center RIA/Biomarkers Core (NIH DK19525). Dr Vorovich was supported by the NIDDK
Medical Student Research Program.
Dr Cappola has received research grants from Abbott Diagnostics and GlaxoSmithKline.
Submitted July 24, 2007; accepted January 15, 2008.
Reprint requests: Thomas P. Cappola, MD, ScM, 6 Penn Tower, 3400 Spruce St.,
Philadelphia, PA 19104.
0002-8703/$ - see front matter
© 2008, Published by Mosby, Inc.
ARTICLE IN PRESS
mask associations of interest, although studies in healthy
subjects done by Tayebjee et al23indicate that diurnal
variation is unlikely.
In conclusion, our findings do not support the use of
circulating MMP-9 levels as a clinical biomarker in
systolic heart failure and verify the prognostic value of
BNP in clinical practice. Further research in diverse
patient populations is needed to clarify the utility of
MMPs and other biomarkers of remodeling and heart
failure. Moreover, further defining the mechanistic role
of MMPs in human heart failure will require trials of
specific MMP inhibitors or techniques that allow in vivo
measurement of MMPs within the myocardium in
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