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
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Abstract |
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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
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Introduction |
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Results from large prospective cohort studies suggest that risk of future occurrence of coronary heart disease (CHD) events can be estimated1,2 and that strategies to influence major modifiable risk factors may result in improved mortality and morbidity. Established risk factors account for a substantial proportion of the risk of CHD, yet prediction of future cardiovascular disease (CVD) events is less certain. Parameters reflecting left ventricular dysfunction are amongst the best predictors of recurrent CVD events.3
Attempts to improve predictive accuracy of tests for CVD events have included inflammatory mediators and other biomarkers that reflect aspects of atherothrombotic processes that underlie recurrent events. In the long-term intervention with pravastatin in ischaemic disease (LIPID) study4 we have observed that total white blood cell (WBC) count but not C-reactive protein (CRP), displayed independent predictive power. Inflammatory markers also participate in the process of ventricular remodelling that may occur as a component of CHD or some of its risk factors.
Tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-brain natriuretic peptide (NT-proBNP) have in common that both have been correlated directly with major CVD risk factors: TIMP-1 in the Framingham Offspring Study5 and NT-proBNP in risk stratification in the AtheroGene Study6 both expressed damaged myocardium.7,8 Changes in the integrity of the myocardial extracellular matrix9 as well as in processes that regulate the balance between atheromatous plaque dissolution and stability can lead to increased TIMP-1 expression.10 Myocardial stretch associated with changes in ventricular function stimulates secretion of BNP, which is synthesized as an inactive prohormone and released from the ventricle as active BNP hormone and an inactive N-terminal fragment (NT-proBNP). The prognostic use of BNP has been assessed in heart failure,11 myocardial ischaemia12 and other clinical settings.13 Two recent prospective longitudinal studies demonstrated that raised plasma NT-proBNP in stable CHD was related to long-term mortality.14,15 TIMP-1 has also been shown to be abnormally elevated in the plasma of patients with acute coronary syndromes16,17 and in a 2-year follow-up of men who had undergone coronary angiography.18
The relative strengths of the associations between BNP (or NT-proBNP) and of TIMP-1 as independent predictors of recurrent CVD events in patients with established CHD are unknown. Of further interest is whether treatment with cholesterol lowering agents such as pravastatin influences predictive powers of NT-proBNP and TIMP-1. These issues were examined in a cohort of 500 patients with pre-existing CHD who were enrolled in the much larger LIPID and LIPID extended follow-up studies and who were prospectively monitored for recurrent CVD events of myocardial infarction and cardiovascular death. The potential confounding effects of conventional risk factors and other inflammatory biomarkers (CRP and IL-6) were also analysed.
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Methods |
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Study population
The design of the LIPID Study has been described in detail previously. People aged 31–75 years, who had suffered a myocardial infarction or hospital admission for unstable angina 3–36 months previously entered the LIPID trial if their plasma total cholesterol was 4.0–7.0 mmol/L (155–271 mg/dL) and fasting triglycerides <5.0 mmol/L (<445 mg/dL). Patients were screened in 87 centres in Australia and New Zealand. After an 8-week placebo run-in phase, 9014 patients were randomly allocated to receive pravastatin 40 mg daily or matching placebo. After closure of the placebo-controlled trial and after a mean follow-up of 6 years, all patients still alive were seen in clinic visits (wherever possible) and offered open-label pravastatin 40 mg daily for a further 2 years, irrespective of the original assigned therapy. All deaths, myocardial infarctions, and strokes were reviewed by outcome-assessment committees whose members had no knowledge of the treatment assignment at the commencement of the study.
A study of 500 patients was designed to be an initial pilot investigation to obtain data on potential biomarkers that could form the basis of measurements in the total cohort. The primary analysis was to determine which biomarkers were strongly predictive of future CVD events based on the strengths of their associations on initial univariable analyses. In the LIPID trial sampling of blood was made at baseline and annually during the 6 years of the blinded phase. Since the baseline and 1-year samples have been conserved for analysis of the entire cohort, blood samples that were collected from patients during the placebo-controlled trial and 4–6 years after randomization have been used for this study. Apart from the first 2-yearly samples, adequate volumes for the pilot study were available in years four to six. Subjects were randomly selected using a nested case control design with 250 cases and 250 controls. A case was defined as a patient who had a cardiovascular event at some time point after the collection date of the sample of that patient and during the remainder of the placebo-controlled or open label phases of the LIPID study. This time averaged to 2.5 years. A cardiovascular event was defined as cardiovascular death, non-fatal myocardial infarction or stroke. The time of the event refers to the earliest event during this time period (if more than one occurred) and was measured from the blood collection date. For each case a matched control was selected at random from among all the remaining eligible patients who had not had a cardiovascular event during the same length of follow-up time from blood collection as the matched case.
Laboratory methods
Blood was drawn after a 12-h fast into EDTA tubes. Samples were stored in liquid nitrogen at –70°C until analysis. Plasma NT-proBNP was measured using an electrochemiluminescence sandwich immunoassay (ECLIA, Roche Diagnostics, Mannheim, Germany) on an Elecsys System 2010. Intra- and interassay precision for the luminescence-sandwich-immunoassay were 0.8–3% and 2.2–5.8%, respectively. The linear range of detection of this assay was 5–35 000 pg/mL; cross-reactivity with brain natriuretic peptide and atrial natriuretic peptide was less than 0.001%. Plasma TIMP-1 was measured by single determination using a commercially available two-site ELISA method (Amersham Biosciences Europe). The ELISA determines free TIMP-1 and TIMP-1 complexed with various matrix metalloproteinases. Additional biomarkers were considered with which NT-proBNP and TIMP-1 could be compared; CRP and IL-6, both markers of inflammation with strong reported predictive power were chosen. CRP was determined by a highly sensitive, latex particle-enhanced immunoassay (detection range of 0–20 mg/L, Roche Diagnostics, Mannheim, Germany). High sensitivity IL-6 was determined by an ELISA method (R&D Systems, Germany).
Statistical analysis
The present study was conducted in a nested case–control sample including cases with a recurrent cardiovascular event (n = 250) and approximately matched controls for each case (n = 250), using a blood sample collected between 4 and 6 years after randomization. Mean levels of continuous variables collected at randomization were compared between cases and controls using a paired t-test, after first checking that there was no interaction between the effect of pravastatin and status. For biomarker variables with a skewed distribution, median values are presented and cases and controls were compared using a Wilcoxon signed rank test. An independent sample t-test or a Wilcoxon rank sum test was used to compare biomarker levels between levels of other risk factors, within the control group. Spearman's rank correlation was used to assess the relationship between biomarker variables and baseline variables in the control group only.
Conditional logistic regression analysis for matched case-control studies, matching cases and controls on the same amount of follow-up time, was used to investigate the association between the outcome and the explanatory variables. In these analyses, all the biomarkers were treated as both continuous variables and as quartiles derived from the distribution of the entire population. Four models were considered for assessing the effect of NT-proBNP and TIMP-1: (1) individually as unadjusted values; (2) individually, adjusted for treatment with pravastatin and classical risk factors using the LIPID risk score19 [that includes 13 components with differential weightings according to the importance of the risk factor or the severity of the clinical presentation (such as number of previous myocardial infarctions) at randomization]; (3) together with further adjustment for CRP and IL6, both as quartiles and WBC; and (4) using a model in which the LIPID risk score was replaced by age, multiple prior myocardial infarctions, diabetes mellitus, and prior stroke. The fitted values from the conditional logistic regression were plotted together with the Lowess smooth of these values, and the shape of the smoothed plot was used to determine the form of the relationship of WBC and the lipid risk score and status. As the sample size was small and due to the matched design, it was not possible to assess all of the standard risk factors for CVD events simultaneously, so Model 4 was included, in order to account for the four main baseline characteristics that differentiated cases from controls. The test for trend associated with increasing quartiles of TIMP-1 was estimated using the median for each quartile. Further, the strengths of TIMP-1, NT-proBNP, IL6, and CRP for cardiovascular risk prediction were compared. Conditional logistic regression models were derived using the biomarkers as dichotomous variables and used to explore to what extent NT-proBNP and TIMP-1 might add to the predictive value of the strongest classical risk predictors.
P < 0.05 was considered to be significant. Analyses were carried out as both categorical and continuous variables with highly consistent results and only the former is shown. All analyses were carried out with SAS, version 9.1 (SAS Institute).
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Results |
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The baseline characteristics of the study participants who subsequently developed cardiovascular events (cases) and those who remained free of reported cardiovascular events (controls) are provided in Table 1. Overall, individuals who developed new cardiovascular events were older, heavier, had higher blood pressures and were more likely to have diabetes and a previous history of smoking. They were more likely to have had a myocardial infarct and peripheral arterial disease and to have had multiple infarcts prior to their initial randomization. There were no significant differences between the two groups for total and high-density lipoprotein (HDL) cholesterol but plasma triglycerides were significantly higher among the cases.
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Cardiovascular events
The nature of the events among cases subsequent to the blood sample was as follows. Coronary deaths: 73 (29%); vascular non-coronary deaths: 8 (3%); non-fatal myocardial infarctions: 112 (45%) and non-haemorrhagic stroke: 57 (23%) of cases.
Traditional risk factors and N-terminal pro-brain natriuretic peptide correlates
Circulating NT-proBNP levels for the entire group ranged between 5 and 16 780 pg/mL with a mean value of 689 pg/mL and a median value of 268 pg/mL (117–646, 25th and 75th percentile). The corresponding values for TIMP-1 were 226 to 1654 pg/mL with a mean of 798 (median 772 pg/mL; 25th–75th percentile 672–889 pg/mL). Treatment with pravastatin did not significantly change NT-proBNP or TIMP-1 levels (P = 0.70 and 0.57 respectively). As outlined in Table 2, neither NT-proBNP nor TIMP-1 concentrations in controls or cases were related to a history of diabetes, hypertension, smoking status or adiposity (BMI). TIMP-1 and NT-proBNP increased significantly with age and with CRP values.
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The CRP and IL-6 concentrations are shown in Table 1 and neither differed significantly between cases and controls.
N-terminal pro-brain natriuretic peptide and tissue inhibitor of metalloproteinase-1 concentrations and cardiovascular risk
The concentrations of both NT-proBNP and TIMP-1 were significantly higher among the cases who experienced a recurrent cardiovascular event during follow-up than among those who did not (389 vs.198 pg/mL for NT-proBNP; 808 vs. 736 pg/mL for TIMP-1; P < 0.001 for both; Table 1). As outlined in Table 3, the odds ratio (OR) of recurrent cardiovascular events with increasing quartiles of NT-proBNP and TIMP-1 (Model 1; P for trend<0.0001) were such that individuals in the highest quartile had a risk about three times higher than those in the lowest quartile (for NT-proBNP 95% CI 1.8–5.1; for TIMP-1 1.6–4.7; P < 0.001 for both).
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The relationships between plasma NT-proBNP and TIMP-1 concentrations and risk of recurrent cardiovascular events were virtually unaltered in analyses that adjusted for both treatment with pravastatin and baseline differences of traditional risk factors according to the LIPID risk score (Model 2; P for trend < 0.001, Table 3). After further adjustment for CRP and IL-6 the relationship between NT-proBNP and TIMP-1 and future recurrent cardiovascular events remained independently significant (P for trend < 0.004 and 0.018 respectively, Model 3). The relationships were unchanged with WBC count in the model. Model 4 resembles Model 3 except that the LIPID score was replaced by the main components that differed significantly between cases and controls, namely age, multiple prior myocardial infarctions, diabetes mellitus and stroke. None of these potential confounders altered the independent relationships between NT-proBNP or TIMP-1 and combined cardiovascular events (P for trend = 0.023 and 0.02 respectively).
As shown in Figure 1, neither CRP nor IL-6 was independently associated with increased risk of cardiovascular events.
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We further explored to what extent the two biomarkers may add to the predictive value of the strongest classical lipid predictor, the total cholesterol/HDL-cholesterol ratio or to that of CRP and IL-6 (Table 4). In these analyses, subjects were classified as being below or above the median for any of the risk factors considered. Increased risk of a cardiovascular event was associated with higher levels of NT-proBNP (panels A, B, and E) and with higher levels of TIMP-1 (panels C, D, and F). NT-proBNP and TIMP-1 each added to the predictive effect of the total/HDL cholesterol ratio and their respective effects remained significant independently of each other. The results were essentially unchanged after adjustment for treatment.
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Analyses of other potential confounders
To place the predictive value of the biomarkers NT-proBNP and TIMP-1 into the context of that obtained from measurements of inflammatory biomarkers other than C-reactive protein, additional analyses were performed (Figure 1). Comparing the fourth vs. the first quartiles, and adjusting for traditional risk factors, NT-proBNP (OR 2.33, 95% CI 1.30–4.17; P = 0.005) and TIMP-1 (OR 2.05, 95% CI 1.13–3.71; P = 0.02) remained independently associated with future cardiovascular risk. Similarly, the relative risk across the quartiles of TIMP-1, which alone was 8.5 (95% CI 3–24; P < 0.001), remained unchanged when WBC count was included and declined only slightly but not significantly when both WBC count and LIPID score were included (OR 5.8; 95% CI 1.9–17.5; P = 0.002).
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Discussion |
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The present findings demonstrate that two biomarkers that have several important cardiovascular functional similarities were strongly and independently associated with increased risk of future cardiovascular events in a population of subjects with preceding stable clinical CHD. Both TIMP-1 and BNP raised the risk between two and three-fold even after adjusting for a comprehensive set of conventional risk factors, a set of components that differed significantly between cases and controls, treatment with a statin and three other established biomarkers CRP, IL-6, and WBC count.
BNP or NT-proBNP measurements are prognostic during acute myocardial infarction (MI)20 and during non-MI episodes of acute coronary syndrome.21 This is likely to be largely due to the associated haemodynamic changes, although ischaemia may augment BNP expression.22 Inflammatory markers such as TIMP-1 are also promising prognostic markers in the setting of acute coronary syndrome because they mirror the extent of acute tissue damage. In the non-acute setting inflammatory markers such as TIMP-1 may be prognostic because they reflect factors that influence the progression of athero-thrombotic plaques. Furthermore TIMP-1 has also been implicated in processes that are involved in ventricular re-modelling6 and may be predictive of chronic heart failure.23,24
Patients with recurrent CVD events had significantly higher plasma NT-proBNP levels than patients who remained free from future events. Kragelund et al.15 reported a similar association between NT-proBNP and mortality that was independent of other risk factors, in patients with stable CHD. Similar findings have been reported by Omland et al.25 A recent report by Blankenberg et al.14 has confirmed the importance of NT-proBNP as an independent and robust predictor of future events in the heart outcomes prevention evaluation (HOPE) study. These findings are consistent with the concept that post-MI impairment of myocardial function proportionally increases NT-proBNP levels and worsens prognosis for recurrent CVD events. Our data are also consistent with previous reports of higher circulating TIMP-1 levels shortly after episodes of acute coronary syndromes.16,17 Recently, Cavusoglu et al.18 reported that TIMP-1 predicted cardiovascular episodes and death during 2 years of observation after coronary angiography and Lubos et al.26 observed higher levels of TIMP-1 in those patients with suspected coronary artery disease who subsequently experienced cardiovascular death compared with those who did not. However the present study is the first to have shown TIMP-1 to be an independent predictor of cardiovascular events in patients with stable ischaemic heart disease. Remodelling of atherosclerotic arteries and of the damaged myocardium, as well as plaque rupture involves degradation of extracellular matrix by metalloproteinases, a process that is opposed by TIMPs.11
Several TIMPs are expressed in myocardium8 and genetic deletion of TIMP-1 demonstrates its role in maintaining ventricular geometry and function.27 On the other hand, adequate management of risk factors including diabetes mellitus leads to lower circulating levels of TIMP-1.28 We postulate that the increased concentrations of TIMP-1 found in plasma in these disease processes reflect a compensatory response to degradative inflammatory enzymes. We had selected to study TIMP-1 from among other circulating TIMPs because more is known about it.
Previous CVD is one of the strongest risk factors for future CVD events because it demonstrates that the patients in question are susceptible to their risk factor profile and the disease process. Risk stratification in a population with increasing need of secondary prevention is still a challenge. Amongst those who have suffered previous CVD, impaired ventricular function as well as plasma levels of NT-proBNP are particularly powerful predictors of recurrent CVD events.29 The results of the present study show that patients who suffered recurrent CVD events were more likely to have had myocardial infarction (MI), especially recurrent infarctions, as the qualifying criterion for the presence of ischaemic heart disease. Nevertheless, neither multiple previous infarctions nor the presence of other risk factors (age, diabetes, overweight and a conventional risk profile) influenced the independent associations between future cardiovascular events and NT-proBNP and TIMP-1 (Model 4 in Table 3).
The positive association between NT-proBNP and high sensitivity C-reactive protein (CRP) demonstrated a potential interaction between natriuretic peptides and inflammatory markers, but CRP was not predictive of recurrent CVD. The reason for the superiority of TIMP-1 over CRP is uncertain but in a recent report by Blankenberg et al.14 in which NT-proBNP was found to predict future events in the HOPE study, CRP was also found to be non-predictive. Increased circulating IL-6, an inflammatory interleukin that has also been identified as predicting future cardiovascular events30 or progression of atherosclerosis31 was found in this study, as with CRP not to reduce the strengths of the associations between future events and the concentrations of NT-proBNP and TIMP-1. Despite the potential interaction between the two biomarkers TIMP-1 and NT-proBNP remained independent in risk prediction, suggesting that their combined use may further enhance the assessment of the risk of recurrent CVD. Comparing both markers, NT-proBNP appeared to be the more powerful.
Pravastatin therapy did not alter NT-proBNP or TIMP-1 levels. On one hand, lower NT-proBNP levels might have been expected in the pravastatin group because the LIPID trial results included a 22% lower rate of death from cardiac failure following pravastatin treatment.4 Many beneficial effects of statins in CHD have been demonstrated beyond cholesterol lowering. They have been shown to improve endothelial function, to exhibit anti-inflammatory properties, and to prevent cardiac hypertrophy. Their potential to decrease oxidative stress32 may attenuate left ventricular remodelling and thus reduce NT-proBNP levels. On the other hand increased concentrations of TIMP-1 have been found in carotid plaques following pravastatin treatment.33 Overall the predictive power of NT-proBNP for recurrent CV events seems to be independent of statin intake.7
Two important limitations should be kept in mind. First, although the sample size was relatively small, the robustness of the predictive power of the two biomarkers that were the subject of the primary analysis, argues strongly for the validity of the findings. The associations between TIMP-1 and BNP and future CVD events remained in a multivariable model that included conventional risk factors, severity of disease and two additional biomarkers that have also been reported to be strongly predictive.
Second, the LIPID trial design did not include objective measurements of left ventricular dysfunction and heart failure. Since both BNP and TIMP-1 are associated with heart failure and left ventricular remodelling the association of these biomarkers with future CVD events may have partly reflected greater prevalence of patients with heart failure among cases. While this would be consistent with the greater number of patients with multiple previous myocardial infarctions among cases than controls, the LIPID score does account for the presence of multiple risk factors.34
This study strongly supports the use of plasma TIMP-1 and NT-proBNP for prognostic purposes. Since statin therapy had no effect on either TIMP-1 or NT-proBNP levels additional studies are required to identify interventions that may address this risk in a more direct manner.
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The LIPID study was coordinated by the National Health and Medical Research Council Clinical Trails Centre, University of Sydney, and conducted under the auspices of the National Heart Foundation of Australia. Although the LIPID study was supported by a grant from Bristol-Myers Squibb, the present biomarker study was initiated, undertaken, and interpreted independently of the sponsor.
Nt-proBNP immunoassays were provided by Roche Diagnostics, Mannheim, Germany.
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Acknowledgements |
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We thank the Principal Investigators and Study Coordinators at the Centres and the patients for their contribution to the study.
Conflict of interest: none declared.
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Footnotes |
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M.J.W. and P.J.N. are equal First Authors. 
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References |
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