European Heart Journal Advance Access published online on February 22, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn007
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The value of N-terminal fragment of brain natriuretic peptide and tissue inhibitor of metalloproteinase-1 levels as predictors of cardiovascular outcome in the LIPID study
1 University of Queensland, Brisbane, Australia
2 Baker Heart Research Institute, Melbourne, Australia
3 NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
4 Department of Medicine II, Johannes Gutenberg University, Langenbeckstr. 1, Mainz 55131, Germany
5 Royal Prince Alfred Hospital, Sydney, Australia
6 Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
7 National Heart Foundation, Melbourne, Australia
8 Innere Abteilung, Bundeswehrzentralkrankenhaus, Koblenz, Germany
9 INSERM U525, Faculte de Medecin Pitie-Salpetriere, Paris, France
Received 1 March 2007; revised 22 August 2007; accepted 7 January 2008.
* Corresponding author. Tel: +49 6131 175169, Fax: +49 6131 175691, Email: blankenberg{at}2-med.klinik.uni-mainz.de
Aims: We sought to determine the association between two major biomarkers, the inactive N-terminal fragment of brain natriuretic peptide (NT-proBNP) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and long-term cardiovascular outcomes in a cohort of subjects who had a myocardial infarction or unstable angina 3–36 months previously.
Methods and results: Plasma NT-proBNP and TIMP-1 were measured in a nested case control study of 250 randomly matched subject pairs enrolled in the long-term intervention with pravastatin in ischaemic disease (LIPID) and LIPID extended follow-up studies. Cases (n = 250) were defined as those who had a cardiovascular death, non-fatal myocardial infarction or stroke during the studies. Controls (n = 250) remained event-free for the same follow-up duration (average 2.5 years) as the matched cases. The relationships between cases and plasma NT-proBNP and TIMP-1 were adjusted for the LIPID risk score, treatment allocation and other biomarkers (CRP, IL-6 and white cell count), and examined using a multivariable conditional logistic regression model. NT-proBNP levels were significantly higher in the cases than in the controls [389 (152–864) vs. 198 (93–416) pg/mL, median (25%–75% percentiles), P < 0.001]. The odds ratio (OR) of recurrent cardiovascular events in individuals in the highest quartile was three times higher than those in the lowest quartile (95% confidence interval (CI) 1.8–5.1; P < 0.001). Similarly, TIMP-1 levels were significantly higher among cases compared with controls (806 vs. 736 pg/mL, median: highest vs. lowest quartile: OR 2.8, 95% CI 1.6–4.7; P < 0.001). After adjustment for the LIPID risk score, treatment with pravastatin and other biomarkers, both NT-proBNP and TIMP-1 predicted cardiovascular events significantly and independently of each other.
Conclusion: The study suggests that in subjects with stable ischaemic disease, NT-proBNP and TIMP-1 are independent predictive markers of coronary heart disease outcome.
Key Words: Brain natriuretic peptide • NT-proBNP • Tissue inhibitor of metalloproteinase-1 • TIMP-1 • Cardiovascular disease • Risk prediction • Pravastatin • Atherosclerosis
M.J.W. and P.J.N. are equal First Authors.
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