Circulating matrix metalloproteinase-2 but not matrix metalloproteinase-3, matrix metalloproteinase-9, or tissue inhibitor of metalloproteinase-1 predicts outcome in patients with congestive heart failure

doi:10.1016/j.ahj.2004.11.016

American Heart Journal

Volume 150, Issue 3, September 2005, Pages 484-487

https://doi.org/10.1016/j.ahj.2004.11.016 Get rights and content

Background

Extracellular matrix remodeling is thought to play an important role in the progression of heart failure (HF). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are matrix-degrading enzymes that have been demonstrated to influence left ventricular properties and serve as targets of potential anti-remodeling agents. Herein we evaluated the potential significance of circulating MMP and TIMP levels in patients with congestive HF (CHF) speculating it may assume prognostic value.

Methods

Serum samples were obtained from 88 consecutive patients attending the outpatient HF clinic and analyzed for MMP-2, -3, -9, and TIMP-1 as well as N-terminal probrain natriuretic peptide (NT-ProBNP). Patients were followed up for the occurrence of either mortality or hospitalizations due to CHF or either of each.

Results

Circulating levels of MMP-2, -9, and TIMP-1 but not of MMP-3 were increased in patients with CHF as compared with age-matched controls. Only MMP-2 and NT-ProBNP levels correlated significantly with New York Heart Association class. Matrix metalloproteinase-2 and NT-ProBNP levels did not correlate. Patients with circulating MMP-2 above 352 ng/mL were 4.2 times more likely to die, 2.2 times more likely to be hospitalized because of CHF, and 2.3 times more likely to experience either of the 2 end points as compared with patients with MMP-2 concentrations below this threshold.

Both MMP-2 and NT-ProBNP were found to be independent predictors of mortality over a 24-month follow-up period.

Conclusions

Matrix metalloproteinase-2 but not MMP-3, -9, or TIMP-1 serum levels is an independent predictor of mortality in patients with CHF.

Section snippets

Materials and methods

We recruited 88 consecutive patients with advanced HF attending the outpatient HF clinic of the Tel Aviv Sourasky Medical Center. Patients with CHF within New York Heart Association (NYHA) functional classes II-IV were included. The local research ethics committee approved the study protocol and all patients gave written informed consent.

At baseline, patients had a full medical history taken, clinical examination performed, and NYHA class assigned. Patients were followed up every 1 to 3 months

Results

Mean age of the study patients was 72 ± 12 years, their median NYHA was 2.8, and their mean ejection fraction was 38% ± 14%. Sixty-three (72%) of the patients were males. Of the total 88 patients, 72 (82%) were receiving either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 33 (38%) were on spironolactone, 58 (66%) were on β-blockers, and 24 (21%) were receiving digoxin.

Matrix metalloproteinase-2 serum levels significantly correlated with age (r = 0.33, P < .01,

Discussion

We have found that MMP-2, -9, and TIMP-1 serum levels were increased in patients with CHF as compared with control subjects. Levels of MMP-2 but not of the other MMPs or TIMP-1 correlated with the clinical status of the patients exhibited by their NYHA scores. These findings are in line with a recent publication,⁹ yet partially discordant with a study from Wilson et al¹⁰ showing that MMP-2 levels did not differ between patients with CHF and subjects with nonfailing hearts. These apparent

References (13)

G. Klappacher et al.
Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis
Am J Cardiol
(1995)
E.M. Wilson et al.
Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure
J Card Fail
(2002)
R. Visse et al.
Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure. Function, and biochemistry
Circ Res
(2003)
F.G. Spinale
Matrix metalloproteinases: regulation and dysregulation in the failing heart
Circ Res
(2002)
Y.Y. Li et al.
Differential expression of tissue inhibitors of metalloproteinases in the failing human heart
Circulation
(1998)
Z. Gunja-Smith et al.
Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Role of metalloproteinases and pyridinoline cross-links
Am J Pathol
(1996)

There are more references available in the full text version of this article.

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¹: Affiliated to the Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel.

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Clinical InvestigationCongestive Heart FailureCirculating matrix metalloproteinase-2 but not matrix metalloproteinase-3, matrix metalloproteinase-9, or tissue inhibitor of metalloproteinase-1 predicts outcome in patients with congestive heart failure

Background

Methods

Results

Conclusions

Section snippets

Materials and methods

Results

Discussion

Am J Cardiol

J Card Fail

Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure. Function, and biochemistry

Circ Res

Matrix metalloproteinases: regulation and dysregulation in the failing heart

Circ Res

Differential expression of tissue inhibitors of metalloproteinases in the failing human heart

Circulation

Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Role of metalloproteinases and pyridinoline cross-links

Am J Pathol

Clinical Investigation
Congestive Heart Failure
Circulating matrix metalloproteinase-2 but not matrix metalloproteinase-3, matrix metalloproteinase-9, or tissue inhibitor of metalloproteinase-1 predicts outcome in patients with congestive heart failure