* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Tissue inhibitor
Survey
Document related concepts
Electrocardiography wikipedia , lookup
Rheumatic fever wikipedia , lookup
Hypertrophic cardiomyopathy wikipedia , lookup
Remote ischemic conditioning wikipedia , lookup
Coronary artery disease wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Heart arrhythmia wikipedia , lookup
Heart failure wikipedia , lookup
Dextro-Transposition of the great arteries wikipedia , lookup
Transcript
This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy 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 Author's personal copy 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 Author's personal copy 390 S. Frantz et al. / European Journal of Heart Failure 10 (2008) 388–395 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). Author's personal copy S. Frantz et al. / European Journal of Heart Failure 10 (2008) 388–395 391 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. Author's personal copy 392 S. Frantz et al. / European Journal of Heart Failure 10 (2008) 388–395 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. Author's personal copy S. Frantz et al. / European Journal of Heart Failure 10 (2008) 388–395 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 Author's personal copy 394 S. Frantz et al. / European Journal of Heart Failure 10 (2008) 388–395 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. References [1] Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 2007;87:1285–342. [2] Sundstrom J, Evans JC, Benjamin EJ, Levy D, Larson MG, Sawyer DB, et al. Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: the Framingham Heart Study. Circulation 2004;109:2850–6. [3] Matsunaga T, Abe N, Kameda K, Hagii J, Fujita N, Onodera H, et al. Circulating level of gelatinase activity predicts ventricular remodeling in patients with acute myocardial infarction. Int J Cardiol 2005;105:203–8. [4] Squire IB, Evans J, Ng LL, Loftus IM, Thompson MM. Plasma MMP9 and MMP-2 following acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of left ventricular dysfunction. J Card Fail 2004;10:328–33. [5] Wagner DR, 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. [6] Webb CS, Bonnema DD, Ahmed SH, Leonardi AH, McClure CD, Clark LL, et al. Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: relation to left ventricular remodeling. Circulation 2006;114:1020–7. [7] Tziakas DN, Chalikias GK, Hatzinikolaou EI, Stakos DA, Tentes IK, Kortsaris A, et al. N-terminal pro-B-type natriuretic peptide and matrix Author's personal copy S. Frantz et al. / European Journal of Heart Failure 10 (2008) 388–395 [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] metalloproteinases in early and late left ventricular remodeling after acute myocardial infarction. Am J Cardiol 2005;96:31–4. George J, Patal S, Wexler D, Roth A, Sheps D, Keren G. 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. Am Heart J 2005;150: 484–7. Tziakas DN, Chalikias GK, Papaioakeim M, Hatzinikolaou EI, Stakos DA, Tentes IK, et al. Comparison of levels of matrix metalloproteinase-2 and -3 in patients with ischemic cardiomyopathy versus nonischemic cardiomyopathy. Am J Cardiol 2005;96:1449–51. Wilson EM, Gunasinghe HR, Coker ML, Sprunger P, Lee-Jackson D, Bozkurt B, et al. Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure. J Card Fail 2002;8:390–8. Jordan A, Roldan V, Garcia M, Monmeneu J, de Burgos FG, Lip GY, et al. Matrix metalloproteinase-1 and its inhibitor, TIMP-1, in systolic heart failure: relation to functional data and prognosis. J Intern Med 2007;262: 385–92. Creemers EE, Davis JN, Parkhurst AM, Leenders P, Dowdy KB, Hapke E, et al. Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice. Am J Physiol Heart Circ Physiol 2003;284: H364–71. Cavusoglu E, Ruwende C, Chopra V, Yanamadala S, Eng C, Clark LT, et al. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction. Am Heart J 2006;151:1101 e1–8. Lubos E, Schnabel R, Rupprecht HJ, Bickel C, Messow CM, Prigge S, et al. Prognostic value of tissue inhibitor of metalloproteinase-1 for cardiovascular death among patients with cardiovascular disease: results from the AtheroGene study. Eur Heart J 2006;27:150–6. Martos R, Baugh J, Ledwidge M, O'Loughlin C, Conlon C, Patle A, et al. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 2007;115:888–95. Tayebjee MH, Nadar S, Blann AD, Gareth Beevers D, MacFadyen RJ, Lip GY. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Am J Hypertens 2004;17:764–9. Noji Y, Shimizu M, Ino H, Higashikata T, Yamaguchi M, Nohara A, et al. Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction. Circ J 2004;68:355–60. Kotlyar E, Vita JA, Winter MR, Awtry EH, Siwik DA, Keaney Jr JF, et al. The relationship between aldosterone, oxidative stress, and inflammation in chronic, stable human heart failure. J Card Fail 2006;12:122–7. Yan AT, Yan RT, Spinale FG, Afzal R, Gunasinghe HR, Arnold M, et al. Plasma matrix metalloproteinase-9 level is correlated with left ventricular volumes and ejection fraction in patients with heart failure. J Card Fail 2006;12:514–9. Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006;113:2089–96. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, et al. Guidelines for the diagnosis and treatment of chronic heart failure: exe- [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] 395 cutive summary (update 2005): the task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur Heart J 2005;26:1115–40. Gerlach RF, Demacq C, Jung K, Tanus-Santos JE. Rapid separation of serum does not avoid artificially higher matrix metalloproteinase (MMP)9 levels in serum versus plasma. Clin Biochem 2007;40:119–23. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29–36. Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148:839–43. Rohde LE, Ducharme A, Arroyo LH, Aikawa M, Sukhova GH, LopezAnaya A, et al. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation 1999;99:3063–70. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 2000;106:55–62. Li YY, Feldman AM, Sun Y, McTiernan CF. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 1998;98:1728–34. Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T, et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 2000;102:1944–9. Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, et al. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 2001;104:1147–52. Tyagi SC, Kumar SG, Haas SJ, Reddy HK, Voelker DJ, Hayden MR, et al. Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol 1996;28:1415–28. Siwik DA, Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium. Heart Fail Rev 2004;9:43–51. Xu XP, Meisel SR, Ong JM, Kaul S, Cercek B, Rajavashisth TB, et al. Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages. Circulation 1999;99:993–8. Banfi C, Cavalca V, Veglia F, Brioschi M, Barcella S, Mussoni L, et al. Neurohormonal activation is associated with increased levels of plasma matrix metalloproteinase-2 in human heart failure. Eur Heart J 2005;26: 481–8. Ohtsuka T, Hamada M, Saeki H, Ogimoto A, Hara Y, Shigematsu Y, et al. Serum levels of matrix metalloproteinases and tumor necrosis factoralpha in patients with idiopathic dilated cardiomyopathy and effect of carvedilol on these levels. Am J Cardiol 2003;91:1024–7 A8. Altieri P, Brunelli C, Garibaldi S, Nicolino A, Ubaldi S, Spallarossa P, et al. Metalloproteinases 2 and 9 are increased in plasma of patients with heart failure. Eur J Clin Invest 2003;33:648–56. Schwartzkopff B, Fassbach M, Pelzer B, Brehm M, Strauer BE. Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy. Eur J Heart Fail 2002;4:439–64.