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(Circulation. 2000;101:2149.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Elevation of Tumor Necrosis Factor- and Increased Risk of Recurrent Coronary Events After Myocardial Infarction

Paul M. Ridker, MD; Nader Rifai, PhD; Marc Pfeffer, MD; Frank Sacks, MD; Serge Lepage, MD; Eugene Braunwald, MD; for the Cholesterol And Recurrent Events (CARE) Investigators

From the Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (P.M.R.), the Center for Cardiovascular Prevention (P.M.R.), Division of Cardiovascular Diseases (P.M.R., M.P., F.S., E.B.) and the Division of Preventive Medicine (P.M.R.), Brigham and Women’s Hospital; the Department of Pathology, Children’s Hospital Medical Center (N.R.), Harvard Medical School, Boston, Mass; and the Centre Universitaire de Sante de l’Estrie (S.L.), Sherbrooke, Quebec, Canada.

Correspondence to Dr Paul M. Ridker, Cardiovascular Diseases, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115.

	Abstract

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Background—Levels of tumor necrosis factor- (TNF-) increase with acute ischemia. However, whether elevations of TNF- in the stable phase after myocardial ischemia (MI) are associated with increased risk of recurrent coronary events is unknown.

Methods and Results—A nested case-control design was used to compare TNF- levels obtained an average of 8.9 months after initial MI among 272 participants in the Cholesterol And Recurrent Events (CARE) trial who subsequently developed recurrent nonfatal MI or a fatal cardiovascular event (cases) and from an equal number of age- and sex-matched participants who remained free of these events during follow-up (controls). Overall, TNF- levels were significantly higher among cases than controls (2.84 versus 2.57 pg/mL, P=0.02). The excess risk of recurrent coronary events after MI was predominantly seen among those with the highest levels of TNF-, such that those with levels in excess of 4.17 pg/mL (the 95th percentile of the control distribution) had an 3-fold increase in risk (RR=2.7, 95% CI 1.4 to 5.2, P=0.004). Risk estimates were independent of other risk factors and were similar in subgroup analyses limited to cardiovascular death (RR=2.1) or to recurrent nonfatal MI (RR=3.2).

Conclusions—Plasma concentrations of TNF- are persistently elevated among post-MI patients at increased risk for recurrent coronary events. These data support the hypothesis that a persistent inflammatory instability is present among stable patients at increased vascular risk. Novel therapies designed to attenuate inflammation may thus represent a new direction in the treatment of MI.

Key Words: inflammation • myocardial infarction • tumor necrosis factor • atherosclerosis

	Introduction

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Tumor necrosis factor- (TNF-) is a multifunctional circulating cytokine derived from endothelial and smooth muscle cells as well as macrophages associated with coronary atheroma.^{1 2 3} Initially identified as a factor that promoted hemorrhagic necrosis in transplanted tumors,⁴ TNF- is involved in several cardiovascular processes. For example, TNF- levels are markedly elevated in advanced heart failure,^{5 6} and in experimental settings, TNF- can produce left ventricular dysfunction,⁷ pulmonary edema,^{8 9} and cardiomyopathy.¹⁰ Furthermore, TNF- is upregulated in the myocardium in response to both transient myocardial ischemia and reperfusion,^{11 12 13 14} and it has been hypothesized that persistent overexpression of TNF- after ischemia might lead to adverse coronary outcomes.¹⁵ However, although some studies suggest that TNF- levels increase acutely with coronary ischemia,^{16 17} it is unknown whether elevations of TNF- measured several months after myocardial infarction (MI) are associated with increased risk of recurrent coronary events.

To address this hypothesis, we measured circulating TNF- levels among post-MI patients enrolled in the Cholesterol And Recurrent Events (CARE)¹⁸ trial who were prospectively monitored for incident events of recurrent MI and coronary death. Specifically, we evaluated post-MI TNF- levels in a nested case-control analysis involving 272 CARE study participants who subsequently suffered recurrent coronary events (cases) and among 272 age- and sex-matched study participants who remained free of recurrent coronary disease during a 5-year follow-up period (controls).

	Methods

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Study participants were patients enrolled in the CARE trial, a randomized, double-blind, placebo-controlled evaluation of 40 mg of pravastatin daily in the secondary prevention of cardiovascular disease conducted among 4159 individuals with a prior history of MI.¹⁷ Post-MI patients aged 21 to 75 years were eligible for CARE if the qualifying index event occurred 3 to 20 months before randomization and if they had left ventricular ejection fraction >25% and no clinical evidence of congestive heart failure. The primary end point of CARE was death due to coronary heart disease or nonfatal MI confirmed by creatine kinase enzyme measurements. Blood samples were collected in CARE during prerandomization visits designed primarily to determine baseline lipid levels; to be eligible for randomization, levels of total cholesterol were required to be <240 mg/dL and levels of LDL cholesterol were required to be between 115 and 175 mg/dL. On average, prerandomization blood samples were obtained 8.9 months after the qualifying acute MI. Samples were collected in EDTA and stored at -80°C until the time of analysis.

To evaluate the potential role of TNF- as a marker of coronary risk in the CARE study population, prerandomization blood samples were assayed for this cytokine among 272 study participants who subsequently developed recurrent MI or death due to coronary heart disease during study follow-up (cases) and from 272 age- and sex-matched study participants who remained free of recurrent coronary events over a 5-year follow-up period (controls). Stored plasma obtained from each case and control subject was thawed and assayed for TNF- with a commercially available quantitative enzyme immunoassay (Quantikine High Sensitivity human TNF-, R&D Systems). This assay has a lower limit of detection for TNF- of 0.1 pg/mL and a coefficient of variation between 5% and 8%. Blood specimens were analyzed in pairs, with the position of the case specimen varied at random within pairs to reduce systematic bias and limit interassay variability. Laboratory personnel were unaware of case or control status.

The significance of any differences in baseline levels of TNF-, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and blood pressure between case and control subjects was evaluated with the Student’s t test; differences in proportions for other baseline characteristics were evaluated with the ² statistic. Because preliminary data suggested that relationships between TNF- and subsequent risk might be limited to those with high levels in a nonlinear fashion, we conducted evaluations for evidence of association between TNF- and recurrent coronary events among study subjects with levels at baseline above or below the 50th, 75th, 90th, and 95th percentile cut points, as defined by the control values. All analyses of risk took into consideration the matching variables of age and sex. Adjusted estimates of risk were obtained in conditional logistic regression models that further accounted for HDL and LDL cholesterol and triglycerides (lipid-adjusted analysis), as well as for smoking status (current/past/never), body mass index, history of diabetes, diastolic blood pressure, and randomized treatment assignment (fully adjusted analysis). Additional analyses were performed to compute risks across increasing levels of TNF- in which the referent group was those with TNF- levels at or below the 50th percentile of the control distribution. All probability values are 2-tailed, and all confidence intervals were computed at the 95% level.

	Results

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Baseline characteristics of the study participants are shown in Table 1. Due to matching, age (60±9.3 years) and sex distributions (84% male) were similar between case and control subjects. Other baseline characteristics of the study participants are similar to those reported for the CARE trial as a whole; as previously described,¹⁸ those individuals who suffered recurrent coronary events were more likely to smoke, suffer from diabetes, or to have a greater mean body mass index than those who remained free of recurrent coronary events. At study entry, 83% of patients in the CARE trial were taking oral aspirin.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Study Participants

Overall, TNF- levels among study participants were normally distributed (Figure 1). In these data, which derive from frozen plasma samples, the range (95% of values between 0.4 and 4.8 pg/mL), mean (2.7 pg/mL), and median (2.5 pg/mL) TNF- levels were similar to those reported in prior population-based studies based on fresh blood samples (range 0.5 to 4.1 pg/mL; data on file, R&D Systems).

View larger version (11K): [in this window] [in a new window]   Figure 1. Distribution of TNF- among post-MI patients participating in CARE.

Table 2 presents mean TNF- levels among case and control subjects measured at entry into the CARE trial, an average of 8.9 months after the qualifying initial MI. Overall, TNF- levels were significantly higher among those in whom coronary events subsequently developed than among those who remained free of recurrent disease (2.84 versus 2.57 pg/mL, P=0.02). As also shown in Table 2, these differences were present in all low-risk subgroups evaluated, including nonsmokers (2.91 versus 2.56 pg/mL, P=0.008), those without diabetes (2.84 versus 2.54 pg/mL, P=0.02), those without hypertension (2.87 versus 2.61 pg/mL, P=0.05), and those without obesity (3.06 versus 2.62 pg/mL, P=0.02).

View this table: [in this window] [in a new window]   Table 2. Plasma Concentration of TNF- Among Study Participants Who Subsequently Developed a Recurrent Coronary Event (Cases) and Among Those Who Remained Free of Recurrent Coronary Disease During Follow-Up (Controls)

Although mean TNF- levels were significantly higher among cases, the excess risk of recurrent coronary events after MI was predominantly seen among those with the highest levels of TNF-. Specifically, the relative risks associated with TNF- levels exceeding the 50th, 75th, 90th, and 95th percentiles of the control distribution were 1.1 (P=0.7), 1.3 (P=0.2), 1.8 (P=0.02), and 2.7 (P=0.004) (Table 3). Thus, as illustrated in Figure 2, nearly all of the excess risk of recurrent coronary events associated with post-MI TNF- levels was among those with levels >4.17 pg/mL (the 95th percentile cutoff point of the control distribution). Risk estimates were similar in subgroup analyses limited to cardiovascular death (RR=2.1, 95% CI 0.9 to 5.2) or to recurrent nonfatal MI (RR=3.2, 95% CI 1.5 to 6.7).

View this table: [in this window] [in a new window]   Table 3. Crude, Lipid-Adjusted, and Fully Adjusted Relative Risks of Recurrent Coronary Events According to Baseline Plasma Concentrations of TNF- Above the 50th, 75th, 90th, and 95th Percentile Cut Points of the Control Distribution

View larger version (12K): [in this window] [in a new window]   Figure 2. Relative risk of death and recurrent nonfatal MI among participants in the CARE trial according to baseline levels of TNF-. Data are analyzed in 4 groups, with the referent group being those with levels of TNF- less than or equal to the 50th percentile of the control distribution.

We found no evidence of association in these data between TNF- levels and total cholesterol or LDL cholesterol, although small correlations were observed between TNF- and HDL cholesterol (r=-0.10, P=0.03) and triglycerides (r=0.12, P=0.01). There were no significant correlations between TNF- and systolic (r=0.02, P=0.7) or diastolic (r=-0.03, P=0.5) blood pressure, nor were there significant differences in mean TNF- levels for those with and without diabetes (2.8 versus 2.7 pg/mL, P=0.3) or for those who did and did not smoke (2.7 versus 2.6 pg/mL, P=0.4). As shown in Table 3, adjustment for lipid fractions had no impact on the relative risk of recurrent coronary events associated with elevated levels of TNF-, such that those with levels above the 95th percentile of the control distribution had a lipid-adjusted relative risk 2.5 times higher than those with lower levels of TNF- (95% CI 1.3 to 5.0, P=0.007). Similarly, after further adjustment for body mass index, diabetes, and blood pressure (in addition to the matching variables of age and sex), an 2.5-fold increase in risk was observed for those with high levels of TNF- (fully adjusted RR=2.5, 95% CI 1.3 to 5.1, P=0.008). Additional control for randomized treatment assignment and for aspirin use had no effect on these findings; however, because the observed excess risk associated with TNF- was limited to those with the highest levels, the power in this study to detect evidence of an interaction between pravastatin use, levels of TNF- above the 95th percentile, and the risk of recurrent clinical events is low.

In a previous report from this cohort,¹⁹ plasma levels of C-reactive protein (CRP) and serum amyloid A (SAA), 2 nonspecific markers of inflammation, were found to be elevated among those at risk for recurrent coronary events. In these data, modest but statistically significant correlations were observed between TNF- levels and both log-normalized concentration of CRP (r=0.21, P=0.001) and log-normalized concentration of SAA (r=0.18, P=0.001). However, in multivariate analyses that adjusted for both CRP and SAA, the relative risk of recurrent coronary events associated with elevated levels of TNF- remained statistically significant (RR=2.3, 95% CI 1.1 to 4.5, P=0.02); by contrast, the relationship between CRP or SAA and risk of recurrent coronary events was no longer significant after adjustment for TNF- (P=0.6 and 0.5 for CRP and SAA, respectively).

	Discussion

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These data indicate that plasma concentration of TNF-, a multifunctional cytokine with diverse systemic effects, is elevated many months after MI among individuals at increased risk for recurrent coronary events. Specifically, in these data for which blood samples were obtained a minimum of 3 months after initial infarction (mean 8.9 months), those individuals with the highest levels of TNF- were found to have a 3-fold increase in the risk of recurrent MI or coronary death (RR=2.7, 95% CI 1.4 to 5.2, P=0.004). This increased risk was present in all subgroups evaluated, including nonsmokers and those without obesity, 2 factors known to increase TNF- levels. In this regard, the elevated risk associated with elevations of TNF- was independent of other traditional markers of risk evaluated and was present in subgroup analyses limited to the end point of cardiovascular death (RR=2.1) or nonfatal recurrent MI (RR=3.2). The strongest correlates of TNF in these data were CRP and SAA, 2 nonspecific markers of systemic inflammation; however, the increased risk of recurrent coronary events associated with persistent elevations of TNF- was also independent of these latter 2 parameters.

The fact that blood samples were obtained in this study an average of 9 months after MI suggests that the increased risk of recurrent coronary events associated with TNF- is not simply the result of a transient increase in TNF- after coronary occlusion.²⁰ However, the source of persistently elevated levels of TNF- among those at risk in our study is uncertain. Prior studies of acute MI suggest that cytokines are preferentially produced by inflammatory cells in the peri-infarct zone and thus that persistent cytokine elevations result from an increased infiltration of inflammatory cells.²¹ By contrast, in a recent experimental study of MI induced by ligation of the left anterior descending coronary artery in rats, TNF- expression in myocardium was found to persist after infarction even in otherwise normal myocardial segments.¹⁵ In that study, TNF- gene and protein expression persisted in myocytes over time, which suggests a possible long-term role of this cytokine in vascular remodeling. Additional experimental studies will be required to determine the source of the TNF- elevations observed in these data.

Our data demonstrating evidence of persistent inflammation several months after MI among individuals at high risk for recurrent events is consistent with prior work from other investigators indicating persistent elevations of CRP among high-risk individuals recovering from unstable angina²² and extend data demonstrating that both CRP^{19 23 24 25} and interleukin-6²⁶ have predictive value in the setting of acute coronary ischemia. Thus, taken together, these data suggest that subclinical persistent instability, or a susceptibility to recurrent instability, can be detected by the presence of inflammatory markers such as TNF- or CRP, even among apparently stable patients well into clinical recovery.

Potential limitations of our study should be considered. First, plasma concentrations of TNF- increase with both smoking and obesity, and thus it is possible that the current results reflect confounding by these factors. We believe this is unlikely, however, because statistically significant differences in baseline TNF- levels were observed between case and control subjects in subgroup analyses that specifically excluded such individuals. Furthermore, in multivariate analysis, adjustment for these factors had no discernable impact on our results. Second, because our study relied on frozen plasma samples, we cannot exclude the possibility that protein degradation may have affected our study. However, as shown in Figure 1, the TNF- levels observed in our data are similar to those reported in prior studies that used fresh blood samples. Furthermore, even if protein degradation was a problem in our study, this effect could not have lead to any systematic bias because samples from case and control subjects were obtained at baseline and were handled identically throughout the collection, storage, and analytic phases of this analysis. Third, prior data have demonstrated that those individuals with evidence of severely reduced ejection fraction and clinical heart failure have markedly elevated levels of TNF-.^{5 6} Thus, differential levels of ventricular dysfunction after MI among case and control subjects must be considered as an alternative explanation for our results. However, because the CARE trial specifically excluded individuals with any evidence of clinical congestive heart failure, the possibility that systematic differences in ventricular function had a major influence on these data also seems unlikely. Finally, we recognize that the plasma half-life of TNF- is brief and that basal levels are low in most patients. However, these effects would not result in a false-positive finding. Moreover, our data for TNF- are in concordance with recent work in unstable angina that indicates that levels of interleukin-1 receptor antagonist and interleukin-6 are in turn associated with increased risk of in-hospital coronary events.²⁷

Previous investigators have suggested that persistence of TNF- into the late stages of MI may contribute to cardiac myocyte loss and cardiac decompensation.¹⁵ In our data, those individuals with elevated levels of TNF- were at increased risk for coronary death and recurrent MI. Thus, these data are consistent with the hypothesis that inflammation plays a major role in the acute coronary syndromes,^{28 29} as well as having long-term prognostic value among apparently stable patients.^{30 31} Finally, because individuals with elevated levels of TNF- were at increased risk independent of other risk factors, these data also support the possibility that novel therapies designed to attenuate the inflammatory response after acute coronary occlusion may represent a new direction in the treatment of MI.^{28 29}

	Acknowledgments

 
This study was supported by grants from the National Heart, Lung, and Blood Institute, Bethesda, Md, and by an Established Investigator Award from the American Heart Association, Dallas, Tex (P.M.R.).

Received September 21, 1999; revision received December 1, 1999; accepted December 10, 1999.

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