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European Journal of Heart Failure 10 (2008) 388 – 395
www.elsevier.com/locate/ejheart
Tissue inhibitor of metalloproteinases levels in patients with chronic heart
failure: An independent predictor of mortality
S. Frantz 1 , S. Störk ⁎,1 , K. Michels, M. Eigenthaler,
G. Ertl, J. Bauersachs, C.E. Angermann
Department of Internal Medicine I / Center of Cardiovascular Medicine, University of Würzburg, Germany
Received 15 January 2007; received in revised form 13 December 2007; accepted 21 February 2008
Abstract
Background: Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in cardiac remodelling. The prognostic utility
of TIMP is unknown in chronic heart failure (CHF).
Aims: We investigated the association of plasma levels of soluble MMP-9 and TIMP-1 with clinical, laboratory and echocardiographic
parameters and estimated their prognostic value in the prediction of all-cause death.
Methods: MMP-9, TIMP-1, tumour necrosis factor-α, and amino-terminal pro-brain natriuretic peptide were measured in 249 consecutively
enrolled CHF patients and 74 healthy individuals.
Results: After adjustment for age, sex and creatinine, levels of TIMP-1 (1640 vs. 735 ng/ml, P b 0.001) but not MMP-9 were elevated in CHF
patients compared to controls. During a median follow-up period of 2.5 years, 66 patients (27%) died. In multivariable Cox regression
models TIMP-1 but not MMP-9 emerged as an independent predictor of all-cause death (hazard ratio per tertile, 3.5; 95% confidence interval
[CI], 2.2–5.1). In addition to the full set of univariately predictive clinical and serological markers, information on TIMP-1 significantly
increased the area under the receiver operating characteristic curve from 0.77 (95% CI, 0.71–0.84) to 0.87 (95% CI, 0.82–0.92).
Conclusion: In stable CHF patients, TIMP-1 but not MMP-9 is of independent and incremental value regarding the prediction of all-cause
death.
© 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Heart failure; Matrix metalloproteinase; Tissue inhibitor of metalloproteinases; Prognosis
1. Introduction
The myocardial extracellular matrix is a highly dynamic
structure, responsive to biological and mechanical stimuli and
subject to continuous reconstruction [1]. Collagen accumulation in the myocardium is characteristic of pathologic hypertrophy and heart failure. Matrix turnover is regulated, amongst
others, by the matrix metalloproteinases (MMPs), a family of
⁎ Corresponding author. Department of Internal Medicine I / Center of
Cardiovascular Medicine, Klinikstraße 6–8, University of Würzburg, 97070
Würzburg, Germany. Tel.: +49 931 201 36147; fax: +49 931 201 70380.
E-mail address: [email protected] (S. Störk).
1
Both authors contributed equally to the work.
enzymes capable of cleaving components of the extracellular
matrix such as collagen or elastin. Elevated MMP-9 plasma
levels are associated with increased LV diastolic dimensions
and increased wall thickness in man [2]. MMP-9 plasma levels
predict the degree of myocardial remodelling and progression
to heart failure after myocardial infarction [3–7]. Various
MMPs were also found to be elevated in non-ischaemic cardiomyopathy [8–10], and MMP-1 levels are associated with
an adverse prognosis in heart failure [11].
The MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs). TIMPs prevent uncontrolled collagen
degradation but may activate growth factors and inhibit
angiogenesis and apoptosis [1]. Targeted deletion of TIMP-1
adversely affected cardiac remodelling following myocardial
1388-9842/$ - see front matter © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2008.02.015
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S. Frantz et al. / European Journal of Heart Failure 10 (2008) 388–395
infarction [12]. In patients with established or suspected
coronary artery disease, TIMP-1 levels were independently
predictive of all-cause mortality, cardiac mortality, and myocardial infarction risk [13,14]. TIMP-1 was associated with
severity of diastolic compromise [15] and left ventricular
mass [16], and was elevated in hypertrophic cardiomyopathy
[17]. Elevated levels of TIMP-1 have been consistently
reported in chronic heart failure (CHF) regardless of the
underlying cause or the type of left ventricular dysfunction
[8,11,15,18,19], and a level N 1200 ng/ml was indicative of
heart failure [20]. However, the available information regarding the prognostic utility of TIMP-1 in heart failure is
controversial. TIMP-1 was not predictive of remodelling [19],
and TIMP-1 levels and outcome in heart failure were not
associated in two smaller studies [8,11].
Prognosis in the individual patient with CHF is uncertain,
but it is important to identify patients for advanced therapy
like devices or transplantation. Additional prognostic parameters are therefore urgently needed. In addition, identification of a prognostic impact of collagen metabolism may give
a hint to pathophysiology. We therefore tested the hypothesis
that MMP-9 and TIMP-1 would independently predict allcause mortality risk in a large cohort of unselected CHF
patients. Further, we estimated their incremental prognostic
value compared with clinical, laboratory and echocardiographic information.
2. Patients and methods
2.1. Study population and study design
Between 06/2002 and 12/2003, the Würzburg Heart Failure
Registry prospectively collected information on 1054 CHF
patients presenting consecutively at one of the two cardiology
hospitals at Würzburg University. For the current analysis, the
first 250 patients were selected. Adult outpatients and inpatients were eligible if they gave written informed consent.
Two groups of patients were eligible. First, patients with
systolic CHF defined as echocardiographic left ventricular
(LV) ejection fraction b 45%, and with typical CHF signs and
symptoms (at least one of the following: raised jugular venous
pressure, peripheral oedema, third heart sound, pulmonary
congestion at clinical examination or chest X-ray) responsive
to CHF therapy. Second, patients with abnormal LV diastolic
filling characteristics, but preserved systolic function (LV
ejection fraction (EF) ≥45%), were also eligible [21]. All
patients underwent a detailed clinical examination. LVEF was
calculated following standard recommendations according to
Simpson's method. Information on medical history and medication was documented, and anthropometric measurements
were performed in a standardised manner.
Seventy five healthy controls of similar age groups were
selected from relatives of the hospital staff. Only subjects
who were free from any medication were eligible.
All participants signed informed consent forms. The study
was approved by the Ethics Committee of the Medical Faculty
389
of Würzburg University and conformed with the principles
outlined in the Declaration of Helsinki. Blood samples from
one patient and one healthy subject were not available for
analysis due to storage failure. Hence, results are reported
for 249 patients and 74 controls. Death from any cause was
ascertained for CHF patients (100% complete) in August 2005
by contacting the patient’s general practitioner to obtain certificates of death or by consulting hospital notes.
2.2. TIMP-1, MMP-9, TNF-α and other laboratory
measurements
Venous blood samples were drawn from participants after
recompensation between 08:00 and 11:00 h. Samples were
centrifuged and plasma and serum stored at −70° until assayed.
Plasma TIMP-1 (Amersham, Germany), MMP-9 and tumour
necrosis factor (TNF)-α (R&D Systems, Abingdon, UK) were
measured in duplicate according to the manufacturer’s protocol
using commercially available assays. The TIMP-1 assay recognises total human TIMP-1, i.e. free TIMP-1 and that complexed with MMPs. The test fully crossreacts with TIMP-1 in
complexes with MMP-1, MMP-3, MMP-2, MMP-9 and
proMMP-9. It does not crossreact with MMP-2. Linearity is
given from 3.1 to 50 ng/ml. Samples with higher concentrations were diluted to achieve exact values. TIMP-1 plasma
samples are stable for at least 3 years when adequately frozen
(personal communication with Amersham). The MMP-9 assay
recognises natural human MMP-9. No cross-reactivity is
observed with all MMPs tested. Linearity is given over a 1:16
range. All samples were diluted accordingly. The minimum
detectable MMP-9 concentration is b 0.156 ng/ml. Plasma
MMP-9 is stable over a long time [22]. All other serum and
plasma parameters including amino-terminal pro-brain natriuretic peptide (NT-proBNP) were measured as part of routine
clinical testing in the central laboratory of the Würzburg University Hospital.
2.3. Data analysis
Normally distributed variables are reported with mean
(standard deviation) and skewed variables with median
(interquartile range). Group comparisons between patients
and healthy controls were made using the independent t-test,
Mann-Whitney U-test and χ2-test as appropriate. Univariable
associations of clinical variables with markers of collagen
turnover and inflammation were investigated using linear
regression models. Natural logarithmic transformation was
used for skewed variables. Trends in covariate-adjusted means
across categories of respective markers were examined by
ANCOVA. Stepwise multiple linear regression (backward
likelihood ratio) was used to investigate the relation of selected
variables with the dependent variable. Age and sex were
forced into all multivariable regression models. Statistical
interactions were examined by introducing the respective
product-term in the model. In tables describing multivariable
regression models, back-transformed values are given to ease
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Table 1
Characteristics of chronic heart failure patients
Variable
n = 249
Age, years
Female sex, n (%)
BMI, kg/m2
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Heart rate, 1/min
Ischaemic aetiology, n (%)
NYHA class, n (%)
I/II
III/IV
Left ventricular end-diastolic diameter, mm
Left ventricular ejection fraction, %
Systolic heart failure ⁎, n (%)
Atrial fibrillation, n (%)
Diabetes, n (%)
Hypertension, n (%)
Current smoker, n (%)
Anaemia ⁎⁎, n (%)
Peripheral oedema, n (%)
Jugular distension, n (%)
ACE inhibitor or ARB, n (%)
Beta blocker, n (%)
Diuretic, n (%)
Statin, n (%)
Antiplatelet therapy or warfarin
65.3 (13.2)
77 (31)
27.3 (4.9)
127 (22)
73 (13)
73 (17)
107 (43)
with 95% confidence interval (CI). To estimate the prognostic
capacity of TIMP-1, receiver operating characteristic (ROC)
curves were constructed and compared [23]. Differences in the
discriminative value between models were estimated by differences in the area under the ROC curve, taking into account
the correlation between models as they were based on the same
cases [24]. Statistical analysis was performed using SPSS
14.0.1.
3. Results
35 (14)/94 (38)
98 (39)/22 (9)
60 (11)
44 (36–55)
147 (59)
61 (25)
77 (31)
145 (58)
40 (16)
70 (28)
96 (39)
27 (11)
201 (81)
166 (67)
207 (83)
89 (36)
193 (77)
Values are mean (SD), median (IQR) or n (%), according to the nature of the
data.
NYHA, New York Heart Association; ACE, angiotensin converting
enzyme; ARB, angiotensin-1 receptor blocking agent.
⁎ Systolic dysfunction: ejection fraction b45%.
⁎⁎ Anaemia: haemoglobin b12 g/dl in women, and b13 g/dl in men.
interpretation. The association of tertiles of TIMP-1, MMP-9,
TNF-α, and NT-proBNP with all-cause mortality was estimated by Cox proportional hazards regression. Univariable
predictive variables (identified by a P-value of b 0.05) were
backward eliminated in stepwise multivariable models. Results in prognostic models are expressed as hazard ratio (HR)
3.1. Patient characteristics
The detailed characteristics of the CHF cohort are listed in
Table 1. Mean age of control subjects was 47 ± 17 years, 48 were
female, and the mean body mass index (BMI) was 25.6 ± 3.3 (all
Pb0.01 compared to patients). Biochemical parameters are
shown in Table 2. Levels of MMP-9 were similar in patients and
controls, between sexes and across NYHA classes (detailed data
not shown). Levels of TIMP-1, TIMP-1/MMP-9 ratio, TNF-α
and NT-proBNP were markedly elevated in CHF (Table 2).
These differences persisted after adjustment for age, sex, and
creatinine (all P b 0.001, respectively). In the CHF patients,
TIMP-1 levels were lower in men compared to women [1510
(1200–2011) vs. 1770 (1411–2317) ng/ml; P = 0.018] but there
was no difference in the healthy controls [756 (657–868) vs.
733 (601–856) ng/ml; P = 0.403]. A close association of TIMP1 levels with age was apparent after adjustment for sex in
healthy subjects and patients (Fig. 1). TIMP-1 levels were
similar in CHF patients with both, impaired and preserved LV
systolic function and were closely associated with NYHA class
(Fig. 2). Further, TIMP-1 was closely related to NT-proBNP
(R2 = 0.59) and TNF-α (R2 = 0.59) in both patients and controls
(P b 0.0001, respectively). By contrast, no such correlation was
present between MMP-9 levels and NT-proBNP, NYHA class,
and TNF-α levels. TIMP-1 levels were lower among patients
receiving statins (P = 0.014) whereas statin treatment did not
affect levels of TNF-α and MMP-9 (P N 0.2, respectively).
Table 2
Comparison of serological markers in chronic heart failure patients and healthy subjects
Parameter
Chronic heart failure patients n = 249
Healthy controls n = 74
P
P⁎
NT-proBNP, pg/ml
TIMP-1, ng/ml
MMP-9, ng/ml
TIMP-1/MMP-9 ratio
TNF-α, pg/ml
Total cholesterol, mg/dl
HDL cholesterol, mg/dl
Fasting glucose, mg/dl
Haemoglobin, g/dl
Creatinine, mg/dl
Uric acid, mg/dl
Sodium, mmol/l
1129 (402–2852)
1640 (1253–2077)
65 (41–110)
26.2 (13.0–44.0)
6.3 (4.5–10.9)
184 (56)
48 (39–59)
114 (98–153)
13.8 (2.7)
1.1 (0.9–1.3)
7.2 (5.9–8.6)
140 (3)
57 (35–118)
735 (643–868)
62 (50–97)
11.0 (7.90–15.71)
1.1 (0.89–1.49)
225 (43)
57 (47–68)
69 (64–78)
14.5 (1.2)
0.9 (0.80–0.93)
5.3 (4.1–6.4)
144 (3)
b0.0001
b0.0001
0.828
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
0.931
b0.0001
b0.001
Values are mean (SD), median (IQR), depending on the nature of the data.
P for crude comparison (Mann–Whitney U-test).
P⁎ for comparison after adjustment for age, sex, and creatinine (ANCOVA).
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Table 3
Regression coefficients from multivariable analysis on determinants of
TIMP-1
Jugular distension, vs. not
Diabetes, vs. not
NT-proBNP, 1 SD = 1228 ng/ml
Serum sodium, 1 SD = 3.4 mmol/l
Haemoglobin, 1 SD = 2.1 g/dl
Left ventricular end-diastolic
volume, 1 SD = 47 ml
Uric acid, 1 SD = 2.1 mg/dl
β†
Multiplicative
change in TIMP-1
P
0.48
0.30
0.30
− 0.19
− 0.21
0.20
1.48 (1.19–1.52)
1.30 (1.10–1.50)
1.30 (1.20–1.40)
0.81 (0.72–0.90)
0.79 (0.69–0.89)
1.20 (1.09–1.31)
0.0015
0.0035
b0.0001
b0.0001
b0.0001
0.0002
0.13
1.13 (1.04–1.22)
0.0050
†
β = coefficient of linear regression; an increase of the independent variable
by 1 unit is associated with a β increase in TIMP-1. Estimates are adjusted
for age and sex.
lysis. The remaining variables explained 57% of the variance of
TIMP-1 in CHF patients (corrected R2). Table 3 also shows the
multiplicative changes in TIMP-1 associated with 1 SD change
in each estimator. Qualitatively similar results were obtained if
analyses were redone using the TIMP-1/MMP-9 ratio.
3.3. Independent prognostic value of TIMP-1
Fig. 1. Association between mean (SD) log plasma total TIMP-1 levels and age
groups in 249 chronic heart failure patients (closed circles) and 74 healthy controls
(open circles), adjusted for sex. P for trend b0.0001 and 0.024, respectively. The
numbers in the table indicate the proportion of subjects per age group.
3.2. Determinants of TIMP-1
In sex and age adjusted linear regression, strong positive
associations with TIMP-1 were observed for NT-proBNP,
creatinine, jugular distension, uric acid, NYHA class, diuretic
treatment, diabetes, peripheral oedema, and TNF-α (listed in
decreasing strength of association). Likewise, strong negative
associations were observed for: haemoglobin, sodium, diastolic and systolic blood pressure, left ventricular enddiastolic
diameter and volume, total cholesterol, and statin treatment.
Table 3 details the result of the multivariable regression ana-
After a median follow-up of 943 days (IQR 268-1117) 66
patients had died (27%). Crude mortality rates in tertiles of
TIMP-1 were (from low to high) 6%, 23%, and 71% (P for
trend b 0.0001), and in tertiles of MMP-9 42%, 26%, and 32 %
(P for trend = 0.247), respectively. In univariable Cox regression, TIMP-1 was a strong predictor of all-cause mortality risk
(HR per tertile, 4.1; 95% CI, 2.7–6.0; P b 0.0001), whereas
MMP-9 was not (HR per tertile, 0.9; 95% CI, 0.7–1.2;
P = 0.482). In multivariable analysis, the adjusted coefficient
for TIMP-1 was modestly attenuated (HR, 3.5; 95% CI, 2.2–
5.1; P b 0.0001). Fig. 3 compares the discriminative utility of
tertiles of TIMP-1, MMP-9, TNF-α, and NT-proBNP with
respective adjustment for the other significant predictors.
TIMP-1 and NT-proBNP but not MMP-9 and TNF-α exhibited
independent prognostic value.
Fig. 2. Mean (SD) log-plasma total TIMP-1 levels, adjusted for age and sex, in 74 healthy controls and 249 patients with systolic and non-systolic heart failure
(HF; left panel), and TIMP-1 levels, adjusted for sex, in patients according to NYHA class (right panel; black bars indicate women, shaded bars indicate men). P
for trend b0.001, respectively.
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Fig. 3. Survival plots from multivariable adjusted Cox regression models showing the association of tertiles of each marker with all-cause mortality. Curves were
estimated by use of the mean values of covariates. Hazard ratios (HR) and P values refer to comparison between highest and lowest tertile. TIMP-1: HR, 8.0;
95% CI, 3.4–20.2; P b 0.0001; adjusted for age, sex, NYHA class, heart failure aetiology, diabetes, smoking, left ventricular end-diastolic volume, body mass
index, NT-pro-BNP; cut-off values for tertiles were b1390, 1391–1917, N1917 ng/ml. MMP-9: HR, 1.1; 95% CI, 0.6–1.9; P = 0.822; adjusted for age, sex,
NYHA class, heart failure aetiology; cut-off values for tertiles were b48.6, 48.7–89.4, N89.4 ng/ml. TNF-α: HR, 1.1; 95% CI, 0.5–2.0; P = 0.882; adjusted for
age, sex, NYHA class, body mass index; cut-off values for tertiles were b4.99, 4.99–8.7, N8.7 pg/ml. NT-proBNP: HR, 6.4; 95% CI, 2.9–14.3; P b 0.0001;
adjusted for age, sex, NYHA class, haemoglobin, creatinine; cut-off values for tertiles were b570, 570–2228, N2228 pg/ml.
3.4. Incremental prognostic value of TIMP-1
From the complete set of univariable predictors, i.e. age,
sex, NYHA class, heart failure aetiology, hypercholesterolaemia, family history of ischaemic heart disease, lung
disease, body mass index, blood pressure, heart rate, ejection
fraction, haemoglobin, creatinine, and NT-proBNP, an area
under the ROC curve of 0.77 (95% CI, 0.71–0.84) was
derived. If information on TIMP-1 was added, the area under
the ROC curve increased to 0.87 (95% CI, 0.82–0.92;
Fig. 4. Left panel: Incremental prognostic value of information on TIMP-1 values. The dashed line indicates the line of indecision. The grey line indicates the area
under the ROC curve (0.77; 95% CI, 0.71–0.84) for a set of clinical and biochemical variables including age, sex, NYHA class, heart failure aetiology,
hypercholesterolemia, positive family history of ischaemic heart disease, lung disease, body mass index, blood pressure, heart rate, ejection fraction,
haemoglobin, creatinine, and NT-proBNP. The black line shows the area under the ROC curve if information on TIMP-1 is added (0.87; 95% CI, 0.82–0.92;
P b 0.05 for comparison between curves). For selection mode of variables see Patients and methods. Right panel: Prognostic value of the combined information
on TIMP-1 and NT-proBNP (levels split at their median), adjusted for age, sex, and NYHA class. P b 0.0001 for comparison between extremes.
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P b 0.05 for comparison between curves; Fig. 4, left panel).
To assess the combined prognostic value of TIMP-1 and NTproBNP, both variables were split at the median and the
combination of “TIMP-1 low, NT-proBNP low” was defined
as referent, i.e. HR 1.00. Patients in the group with “TIMP-1
high, NT-proBNP high” exhibited the highest mortality risk
(HR, 16.6; 95% CI, 8.0–19.1; Fig. 4, right panel).
4. Discussion
TIMP-1 but not MMP-9 was of independent and incremental value for the prediction of all-cause mortality risk in
patients with chronic heart failure. In addition, TIMP-1, but not
MMP-9, was associated with heart failure severity as indicated
by NYHA class and NT-proBNP, with the biomarker of im-
393
mune activation TNF-α, the comorbid conditions diabetes and
renal failure, and the use of statins.
4.1. Independent and incremental prognostic value of
TIMP-1
TIMP-1 emerged as a strong predictor of all-cause death over
a 24 month period. Patients in the highest TIMP-1 tertile had
an eight-fold increase in mortality risk. This effect was robust
against adjustment for potential confounders selected from
clinical and biological risk factors/mediators known to be
associated with increased mortality risk in heart failure. TIMP-1
exhibited incremental prognostic information when added on
top of a summary set of clinical and biochemical CHF descriptors including NT-proBNP. In particular, the combination
Table 4
Studies investigating peripheral TIMP-1 blood levels in patients with heart failure or conditions predisposing to heart failure
Condition studied
Type of study
Jordan A [11]
Author (ref. no.)
50
53
Systolic dysfunction
Follow-up study Composite of
(17.5 months)
all-cause death,
readmission for
heart failure,
cardiac transplant
Martos R [15]
32
54
Diastolic dysfunction
Cross-sectional
–
Ahmed SH [20]
50
53
Cross-sectional
–
Kotlyar E [18]
Yan AT [19]
58
184
0
0
Hypertensive heart
disease
Systolic dysfunction
Systolic dysfunction
George J [8]
88
30
Tziakas DN [7]
52
0
Noji Y [17]
28
50
Tayebjee MH [16]
74
34
Altieri P [35]
51
52
Schwartzkopff B [36]
Wilson EM [10]
43
24
47
48
249
74
Present study
N, patients N, controls
Heart failure of various
causes
Systolic dysfunction
Hypertrophic
cardiomyopathy
Hypertensive heart
disease
Heart failure of various
causes
Dilated cardiomyopathy
(stable CAD) Systolic dysfunction
Endpoints
Main findings
• Associated with peak oxygen
consumption
• Elevated in congestive heart
failure
• Not independently associated
with outcome
• Elevated in diastolic heart failure
• Associated with severity of
diastolic compromise
• Level N1200 ng/ml indicative
of heart failure
• Elevated in heart failure
• Not predictive of remodeling
Cross-sectional –
Follow-up study LV volumes and
(12 months)
ejection fraction
(radionuclide
ventriculography)
Follow-up study Composite of
• Elevated in heart failure
(24 months)
all-cause death
• Not predictive of outcome
and readmission
for heart failure
Cross-sectional –
• Lower in non-ischaemic compared
with ischaemic cardiomyopathy
Cross-sectional –
• Elevated in hypertrophic
cardiomyopathy
Cross-sectional –
• Correlated with left ventricular
mass
Cross-sectional –
• Elevated in heart failure
Cross-sectional –
• Elevated in heart failure
Follow-up study No outcome
• Similar in patients with ischaemic
(12 months)
analysis included and non-ischaemic cardiomyopathy
Elevated in heart failure (stable
during follow-up)
Systolic and non-systolic Follow-up study All-cause death
• Elevated in heart failure
dysfunction; heart failure (30 months)
• TIMP-1, but not MMP-9, of
of any aetiology
independent and incremental
value for the prediction of
mortality risk
• TIMP 1, but not MMP-9,
associated with heart failure
severity, NT-proBNP, TNF-α,
diabetes, renal failure, use of statins
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of high TIMP-1 and high NT-proBNP levels was associated
with a particularly adverse prognosis. One plausible explanation
for this additive detrimental effect may be that NT-proBNP
mainly reflects deteriorated loading conditions, whereas TIMP1 mirrors changes in the extracellular matrix in CHF patients.
sured from peripheral blood are not different between patients
with heart failure and controls, and are not associated with
mortality risk. The reasons for these differences are unclear and
not explained by variation of severity or aetiology of heart
failure, age or sex, between the different studies.
4.2. TIMP-1 and heart failure
4.4. Limitations
The collagen matrix plays a critical role in maintaining the
structural alignment of myocytes and, thus, the left ventricular
geometry. The collagen matrix is tightly regulated by its degrading enzymes, such as different MMPs and the antagonistic
TIMPs. A cause and effect relationship for MMP expression
and left ventricular remodelling has been postulated on
the basis of studies in transgenic mice or through the use of
pharmacologic MMP inhibitors [25,26]. TIMP-1 deficiency
exacerbated left ventricular remodelling after experimental
myocardial infarction [12]. Data on expression patterns of
TIMP-1 in myocardial biopsies of patients with cardiac diseases are inconsistent. Whereas some reports suggested a
decrease [27] or no change [28], others observed an increase of
TIMP-1 levels [29,30] in heart failure patients. By contrast, all
studies investigating TIMP-1 levels from peripheral blood
samples observed elevated levels in heart failure (Table 4). In
a community based sample of healthy men, higher plasma
TIMP-1 levels were associated with increased LV diastolic
dimensions and increased wall thickness [2]. TIMP-1 levels
correlated with diastolic dysfunction in hypertensive patients
[16]. The present study found elevated TIMP-1 levels in
patients with CHF regardless of the type of heart failure, i.e.
systolic or non-systolic. TIMP-1 levels were associated with
the severity of heart failure as indicated by NT-proBNP, NYHA
class, jugular distension, peripheral oedema, the use of diuretics, LV end-diastolic dimension and volume, the latter
keeping its diagnostic utility also in multivariable analysis
(Table 3). In addition, we found a positive association of TIMP1 plasma levels with inflammatory markers as TNF-α, and
lower TIMP-1 levels in patients treated with statins. This is in
accordance with in vitro data where TIMP-1 expression was
regulated by pro-inflammatory proteins [31], and treatment
with 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase
inhibitors reduced TIMP-1 production [32]. Yet, TIMP-1
levels were still two-fold higher compared with controls. In
order to relate TIMP-1 levels to the pathophysiology of CHF,
the source of plasma TIMPs should be evident. One possibility
might be that plasma MMPs/TIMPs represent a spillover from
cardiac MMP/TIMP production into the interstitium. Yet, other
cells as leukocytes or endothelial cells are capable of MMP and
TIMP production as well. Thus, the source of elevated TIMP in
heart failure remains unclear and requires further investigation.
Since this study was cross-sectional, we cannot draw conclusions on a proposed cause and effect relation between
MMP-9 and the course of CHF. However, our data do not
support a prognostic role for MMP-9 in these patients. Since
MMPs constitute a family of enzymes with over 20 different
species, our findings cannot be extrapolated to other MMPs.
Further, collagen degradation products (e.g., pro-collagen type
III N-terminal pro-peptide) were not measured and collagen
metabolism in a stricter sense may therefore not be related to
TIMPs and MMPs in this study.
In summary, we have demonstrated elevated TIMP-1 serum
levels in patients with CHF with both, impaired or preserved
LV function. TIMP-1 levels were closely associated with established markers of CHF severity, parameters of systemic inflammation, markers of myocardial remodelling and all-cause
mortality.
4.3. MMP-9 and heart failure
Some smaller studies have reported elevated MMP-9 expression in patients with heart failure [8,10,28,33,34]. By
contrast, we and others [8] found that levels of MMP-9 mea-
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft (Fr. 1377/4-3, Sonderforschungsbereich 688/TP 10)
and by an unrestricted educational grant by MERCK KGaA,
Darmstadt, Germany. Further support was provided by the
National Heart Failure Network of Competence, funded by the
German Ministry for Education and Research. We thank
M. Leutke and H. Wagner for their excellent technical support.
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