Inflammatory Markers, Angiographic Severity of Coronary Artery Disease, and Patient Outcome

Article Outline

• Abstract
• Methods
• Results
• Discussion
• References
• Copyright

Serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) have been shown to be predictors of adverse outcomes in patients with coronary artery disease (CAD). We hypothesized that measurement of inflammatory markers could predict atherosclerotic burden and major adverse cardiac events (MACEs). We prospectively measured hs-CRP, IL-6, and TNF-α in 249 patients who were admitted with acute chest pain and underwent coronary angiography. We analyzed the relation between serum levels of inflammatory markers and angiographic severity of CAD. A follow-up at 6 months was conducted to assess MACEs, defined as a cumulative of myocardial infarction, all-cause death, or coronary revascularization (percutaneous coronary intervention or coronary artery bypass surgery). After adjusting for conventional CAD risk factors (age, gender, diabetes, hypertension, smoking, and hypercholesterolemia), there was no association between inflammatory markers (hs-CRP, IL-6, and TNF-α) and angiographic severity of CAD. There was a significant positive correlation between age, male gender, diabetes mellitus, and hypercholesterolemia with atherosclerotic burden determined by angiography. There was no significant positive association between MACEs and hs-CRP, IL-6, or TNF-α level in unadjusted and adjusted models. In conclusion, in patients hospitalized with chest pain, we found no association of serum levels of hs-CRP, IL-6, or TNF-α with coronary atherosclerotic burden or MACEs at 6 months after adjustment for traditional CAD risk factors.

Serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) have been shown to be predictors of adverse outcome in patients with coronary artery disease (CAD).¹, ², ³, ⁴, ⁵ However, recent data have been conflicting.⁶, ⁷, ⁸, ⁹, ¹⁰ We hypothesized that measurement of serum markers of inflammation could be useful in estimating atherosclerotic burden in patients with CAD, in particular those who are hospitalized with acute chest pain. In addition, we hypothesized that an increase in serum markers of inflammation (hs-CRP, IL-6, and TNF-α) might correlate with major adverse cardiac events (MACEs).

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Methods 

This prospective study consisted of a series of consecutive patients (men and women, ≥21 years of age) who had a diagnosis of acute chest pain suspected to be of cardiac cause and were admitted to a coronary care unit. We included patients with or without known CAD but excluded those with ST-elevation myocardial infarction. Patients were enrolled in the study within the first 24 hours of admission and evaluated during the index admission, at 6 weeks (±2 weeks) from enrollment, and again at 6 months (±1 month).

Our study was a longitudinal, prospective cohort study. Other than blood sampling for serum measurements detailed in the following, no other intervention was planned as part of this study, and patients were managed by their clinicians as deemed appropriate. The study was approved by the University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System institutional review board. All patients gave informed consent.

Clinical history and physical examination data focusing on characteristics of chest pain and presence of CAD risk factors were recorded for every patient. Serial electrocardiograms and cardiac enzymes were also obtained in all patients. Demographic and clinical information, including age, gender, marital status, race, diabetes mellitus, smoking, hypertension, hyperlipidemia, history of CAD, family history of CAD, and current medications (use of aspirin, β blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, lipid-lowering agents, and antibiotics), were also recorded.

Diabetes mellitus was defined as a previous diagnosis, use of diet or antidiabetic medicines, or a fasting venous blood glucose level ≥126 mg/dl on 2 occasions in previously untreated patients. Patients who received medications for hypertension or those with a systolic blood pressure ≥140 mm Hg and/or a diastolic blood pressure ≥90 mm Hg and not on concurrent antihypertensive therapy were classified as having hypertension. Hypertension in diabetics was defined as a systolic blood pressure ≥130 mm Hg or a diastolic blood pressure ≥80 mm Hg. Patients who smoked within the previous 1 year were deemed current smokers. Patients who used cholesterol-lowering medicines or had a total serum cholesterol level ≥200 mg/dl were classified as having hypercholesterolemia.

Peripheral venous blood samples were collected within the first 24 hours of index hospitalization. Clinical outcome data with regard to MACEs and new-onset congestive heart failure within the index hospital admission and during 6 months of follow-up were collected. A MACE was defined as a cumulative of myocardial infarction, all-cause death, or coronary revascularization (percutaneous coronary intervention or coronary artery bypass surgery). Congestive heart failure was diagnosed if patients met Framingham criteria for congestive heart failure. Follow-up was ascertained by a scheduled clinic visit. If a clinic encounter was not possible, follow-up was done by telephone interviews or review of hospital records. Patients and their families were advised to notify the study center in case of untoward events or admission to an outside medical facility.

Serum samples were sent to a central laboratory for measurement of hs-CRP, IL-6, and TNF-α. High-sensitivity CRP was analyzed by an immunoturbidimetric method (Roche Modular P, Hitachi, Mannheim, Germany), IL-6 by an immunoenzymatic method (Unicel DXI 800, Fullerton, California), and TNF-α by a chemiluminescence method (DPC Immulite 1000, Los Angeles, California). Investigators assessing coronary angiograms and clinical outcomes were blinded to the results of the laboratory measurements.

Coronary angiography was performed in all patients during the index hospitalization. Degree of stenosis was recorded as previously reported.¹¹ Luminal stenosis ≥50% in any of the epicardial coronary arteries (left anterior descending coronary artery, left circumflex artery, or right coronary artery) was considered obstructive. Stenosis <50% was considered nonobstructive. We also subcategorized obstructive angiographic CAD stenosis as the number of coronary arteries with luminal narrowing ≥50% or ≥70%. The number of segments having any coronary artery stenosis (nonobstructive, ≥50% stenosis, or ≥70% stenosis) was also recorded. The classification of arteries into segments has been previously described.¹²

All analyses were performed with SAS 9 (SAS Institute, Cary, North Carolina). Univariate comparisons for equality of means and/or proportions, respectively, were tested using the t test, 1-way analysis of variance, and the chi-square test. Adjusted and unadjusted multivariate models were applied to test associations between inflammatory markers (hs-CRP, IL-6, and TNF-α) and angiographic severity of CAD, MACEs, and new-onset congestive heart failure. We used multivariate linear regression for continuous outcomes, ordinal logistic regression (proportional odds models) for ordinal outcomes, and logistic regression for dichotomous outcome MACEs. In a few models in which proportional odds assumption was not met, we treated outcome as nominal. All associations were considered significant at an α level of 0.05.

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Results 

All 249 patients underwent coronary angiography after admission for chest pain. The inflammatory markers hs-CRP, IL-6, and TNF-α were measured in all patients within 24 hours of admission. Patients were categorized into tertiles according to hs-CRP values <1.00, 1 to 2.99, and ≥3.00 mg/L. Patients were also categorized into 2 groups based on median values of IL-6 (<4.7 and ≥4.7 pg/ml) and TNF-α (<6.2 and ≥6.2 pg/ml).

Patient demographics, baseline characteristics, and conventional risk factors in different groups of patients are listed in Table 1. There were no significant differences in CAD risk factors in different groups, except that there were more white patients in the group with higher TNF-α values, and patients in the TNF-α group with higher values were less likely to have diabetes and more likely to have lower high-density lipoprotein cholesterol values than those with lower TNF-α levels. These differences were believed to be incidental with no clinical relevance.

Table 1. Demographics and baseline characteristics of study population according to various tertiles of high-sensitivity C-reactive protein and subgroups of interleukin-6 and tumor necrosis factor-α (n = 249)

	hs-CRP (mg/L)				IL-6 (pg/ml)			TNF-α (pg/ml)
	<1.00 (n = 188)	1–2.99 (n = 44)	>3.00 (n = 17)	p Value	<4.7 (n = 125)	≥4.7 (n = 124)	p Value	<6.2 (n = 123)	≥6.2 (n = 126)	p Value
Age (yrs)	59.7±10.2	59.5±8.5	60.5±6.7	0.94	60.3±9.4	59.1±10.0	0.31	59.4±9.3	>60.1±10.1	0.59
Men	89.4%	84.1%	94.1%	0.47	95.2%	82.3%	0.001	85.4%	92.1%	0.09
White	87.2%	88.6%	88.2%	0.96	92.0%	83.1%	0.03	82.9%	92.1%	0.03
Hypertension	85.6%	84.1%	76.5%	0.60	85.6%	83.9%	0.70	83.7%	85.7%	0.66
Diabetes mellitus	30.9%	40.9%	23.5%	0.32	36.0%	28.2%	0.19	38.2%	26.2%	0.04
Current smokers	63.1%	70.5%	64.7%	0.66	59.7%	69.4%	0.11	62.3%	66.7%	0.47
Hypercholesterolemia	69.9%	70.5%	68.8%	0.99	77.6%	62.0%	0.008	74.0%	65.9%	0.16
LDL cholesterol (mg/dl)	107.9±31.7	111.3±33.8	102.2±26.3	0.66	107.5±31.5	108.7±31.9	0.79	111.6±32.4	104.6±30.6	0.12
HDL cholesterol (mg/dl)	38.2±14.1	36.4±11.5	39.8±15.4	0.69	37.7±15.7	38.3±11.5	0.74	39.8±15.5	36.1±11.5	0.05
Triglyceride (mg/dl)	242.8±260.3	230.7±160.9	135.6±71.2	0.27	246.8±244.9	220.1±231.9	0.41	226.4±229.8	240.9±247.9	0.66
Total cholesterol (mg/dl)	181.1±45.7	183.4±41.6	165.5±37.8	0.41	180.4±45.2	180.5±44.1	0.99	184.5±47	176.3±41.6	0.18
History of CAD	48.4%	52.2%	52.9%	0.86	53.6%	45.2%	0.18	52.9%	46.0%	0.28
Family history of CAD	29.7%	42.9%	35.3%	0.25	29.3%	35.6%	0.29	29.5%	35.3%	0.34

Values are means ± SDs or percentages of patients.

HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Of 249 patients, 43 developed non–ST-elevation myocardial infarction. Levels of inflammatory markers (hs-CRP, IL-6, and TNF-α) at admission did not differentiate these patients from those who did not develop non–ST-elevation myocardial infarction.

Two hundred ten patients had obstructive disease (≥50%) in ≥1 coronary artery. The relation of inflammatory markers to coronary angiographic stenosis is presented in Table 2, Table 3 and Figure 1. In the unadjusted model, there was no significant association of hs-CRP with the number of coronary arteries showing ≥50% or ≥70% stenosis on angiography. With more comprehensive analysis of epicardial coronary arteries, there was a significant positive association of hs-CRP levels with the number of coronary segments with ≥50% stenosis, the number of coronary segments with ≥70% stenosis, and the total number of coronary segments with any stenosis (obstructive plus nonobstructive stenosed segments). However, after adjustment for conventional risk factors (age, gender, diabetes, hypertension, smoking, and hypercholesterolemia), this association was lost. Similarly, IL-6 was positively associated with the number of coronary arteries with ≥50% stenosis in the unadjusted model, but this association was lost after adjustment for conventional risk factors. In unadjusted and adjusted models, there was no association between IL-6 and the number of coronary artery segments with ≥50% stenosis, the number of coronary segments with ≥70% stenosis, or the total number of coronary segments with any stenosis. In unadjusted and adjusted models, TNF-α did not correlate with atherosclerotic burden.

Table 2. Parameter estimates, SEs, and p values for unadjusted models between inflammatory markers and angiographic coronary artery disease

	No. of Arteries With ≥50% Stenosis		No. of Segments With ≥50% Stenosis		No. of Arteries With ≥70% Stenosis		No. of Segments With ≥70% Stenosis		No. of Obstructive + Nonobstructive Segments
	Beta ± SE	p Value	Beta ± SE	p Value	Beta ± SE	p Value	Beta ± SE	p Value	Beta ± SE	p Value
hs-CRP	−0.105±0.065	0.11	0.199±0.884	<0.001	0.093±0.064	0.15	0.138±0.063	0.03	0.286±0.124	<0.001
IL-6	0.634±0.237	0.007	−0.338±0.324	0.29	−0.418±0.237	0.08	−0.048±0.232	0.84	−0.821±0.455	0.07
TNF-α	−0.252±0.231	0.27	0.198±0.318	0.53	0.181±0.232	0.61	0.172±0.228	0.45	0.464±0.447	0.29

Table 3. Parameter estimates, SEs, and p values for adjusted models between inflammatory markers and angiographic coronary artery disease after adjusting for conventional risk factors

	No. of Arteries With ≥50% Stenosis		No. of Segments With ≥50% Stenosis		No. of Arteries With ≥70% Stenosis		No. of Segments With ≥70% Stenosis		No. of Arteries With Obstructive and Nonobstructive Disease
	Beta ± SE	p Value	Beta ± SE	p Value	Beta ± SE	p Value	Beta ± SE	p Value	Beta ± SE	p Value
hs-CRP	0.051±0.037	0.16	0.114±0.079	0.15	0.041±0.038	0.28	0.079±0.059	0.18	0.173±0.113	0.12
IL-6	−0.179±0.140	0.20	0.155±0.301	0.61	−0.044±0.144	0.76	0.268±0.222	0.23	−0.185±0.427	0.66
TNF-α	0.125±0.134	0.35	0.091±0.288	0.75	0.078±0.138	0.57	0.073±0.212	0.73	0.213±0.408	0.60
Age	0.019±0.007	0.004	0.063±0.015	<0.0001	0.013±0.007	0.059	0.028±0.011	0.01	0.082±0.021	<0.0001
Men	0.647±0.219	0.003	1.365±0.472	0.004	0.712±0.226	0.002	1.032±0.348	0.003	2.624±0.667	<0.0001
Diabetes mellitus	0.323±0.145	0.026	0.415±0.312	0.18	0.202±0.149	0.176	0.173±0.229	0.45	0.856±0.441	0.05
Hypertension	0.242±0.188	0.19	0.695±0.405	0.09	0.116±0.194	0.55	0.511±0.298	0.09	0.577±0.573	0.31
Smoking	0.079±0.139	0.57	0.175±0.299	0.56	−0.052±0.143	0.71	−0.224±0.220	0.31	0.611±0.422	0.15
Hypercholesterolemia	0.607±0.152	<0.0001	1.089±0.328	0.0009	0.521±0.157	0.0009	0.607±0.241	0.01	1.014±0.463	0.028

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• Figure 1. 

  Mean values of various coronary angiographic indexes across categories of hs-CRP, IL-6, and TNF-α.

In the adjusted model, we found a positive correlation between age, male gender, diabetes mellitus, and hypercholesterolemia and atherosclerotic burden (number of coronary arteries with ≥50% stenosis and total coronary segments with any stenosis). Importantly, we found no association between smoking or hypertension and angiographic coronary narrowing.

Of 249 patients, 4 were lost to follow-up; thus, the remaining 245 patients had complete follow-up at 6 months. Fifty-five of 245 patients had MACEs over the ensuing 6 months, not including the initial hospitalization. There were 66 events (7 deaths, 6 myocardial infarctions, 23 percutaneous coronary interventions, and 30 coronary artery bypass surgeries) in 55 patients during this period. There was no significant positive association between hs-CRP, IL-6, or TNF-α with MACEs in the unadjusted (Table 4) and adjusted (Table 5) models. Fourteen of 245 patients who had complete 6-month follow-up developed new congestive heart failure. There was no relation between serum hs-CRP or TNF-α levels with onset of heart failure over the 6-month follow-up period in the unadjusted (Table 4) or adjusted (Table 5) model.

Table 4. Parameter estimates, SEs, odds ratios, confidence intervals, and p values for unadjusted models between inflammatory markers and major adverse cardiac events and congestive heart failure over six months

	MACEs				CHF
	Beta ± SE	OR	95% CI	p Value	Beta ± SE	OR	95% CI	p Value
hs-CRP	0.063±0.090	1.06	0.892–1.271	0.49	0.454±0.387	1.57	0.738–3.364	0.24
IL-6	−1.148±0.340	0.32	0.163–0.618	0.0007	−1.461±0.679	0.23	0.061–0.878	0.03
TNF-α	0.133±0.321	1.14	0.609–2.144	0.68	0.712±0.597	2.04	0.632–6.574	0.23

CHF = congestive heart failure.

Table 5. Parameter estimates, SEs, odds ratios, confidence intervals, and p values for adjusted models between inflammatory markers and major adverse cardiac events and congestive heart failure over six months after adjusting for conventional risk factors

	MACEs				CHF
	Beta ± SE	OR	95% CI	p Value	Beta ± SE	OR	95% CI	p Value
hs-CRP	0.078±0.098	1.08	0.891–1.311	0.43	0.599±0.479	1.82	0.712–4.663	0.21
IL-6	−0.898±0.369	0.41	0.198–0.840	0.01	−1.354±0.801	0.26	0.054–1.242	0.09
TNF-α	−0.049±0.353	0.95	0.476–1.903	0.89	0.878±0.694	2.40	0.617–9.377	0.21
Diabetes mellitus	0.046±0.402	1.05	0.476–2.302	0.91	0.047±0.895	1.05	0.181–6.058	0.96
Hypertension	0.429±0.487	1.54	0.592–3.989	0.38	1.839±0.771	6.29	1.389–28.483	0.017
Age	0.005±0.019	1.01	0.969–1.043	0.77	0.011±0.036	1.01	0.943–1.048	0.75
Men	0.823±0.509	2.28	0.839–6.176	0.11	0.759±0.789	2.14	0.455–1.023	0.34
Smoking	−0.937±0.397	0.39	0.180–0.854	0.018	0.738±0.682	2.09	0.549–7.968	0.28
Hypercholesterolemia	0.921±0.646	2.51	0.709–8.911	0.15	0.180±1.197	1.19	0.115–12.512	0.88
Aspirin	−0.997±0.553	0.37	0.125–1.092	0.07	−2.166±1.299	0.11	0.009–1.463	0.09
Statins	−0.7951±0.6220	0.45	0.133–1.528	0.20	0.603±1.195	1.83	0.176–19.003	0.61
Angiotensin-converting enzyme inhibitors	−0.2186±0.3739	0.80	0.386–1.672	0.56	0.283±0.779	1.33	0.288–6.114	0.72
Angiotensin receptor blockers	0.2970±1.1698	1.35	0.136–13.33	0.79	−1.120±1.421	0.33	0.020–5.288	0.43
β Blockers	−0.1687±0.4065	0.84	0.381–1.874	0.68	0.148±0.819	1.16	0.233–5.775	0.86

Abbreviation as in Table 4.

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Discussion 

We embarked on this prospective study to establish a relation of inflammatory markers with angiographically documented coronary atherosclerosis. Because IL-6 and TNF-α induce CRP synthesis,¹³ we measured IL-6 and TNF-α levels in addition to hs-CRP levels in serum. We did an extensive, careful analysis of coronary angiograms and quantitation of atherosclerotic burden. Although hs-CRP and IL-6 were associated with some parameters of atherosclerotic burden in the unadjusted model, this association between inflammatory markers and atherosclerotic burden was lost after adjustment for conventional CAD risk factors (e.g., age, gender, diabetes mellitus, hypertension, smoking, and hypercholesterolemia). This observation suggests that the apparent univariate association of hs-CRP and IL-6 with angiographic severity of CAD is due to their association with CAD risk factors and not with coronary atherosclerosis directly. Further, there was no association between TNF-α levels and any angiographic parameter of atherosclerotic burden. Next, we examined the relation of hs-CRP and TNF-α levels with MACEs in our patient population and found no positive association.

Danesh et al⁸ performed a meta-analysis of 22 prospective studies published from 1996 to 2003 that examined the value of hs-CRP as a predictor of adverse cardiovascular events. These studies used hs-CRP as a marker of inflammation, and almost all of the studies were adjusted for at least some CAD risk factors. The combined multivariate adjusted odds ratio (OR) for adverse cardiovascular events was 1.58 (95% confidence interval [CI] 1.48 to 1.68).⁸ Studies published since this meta-analysis have shown a similarly low adjusted relative risk for hs-CRP.⁹, ¹⁴, ¹⁵ Only recently have negative studies also appeared in literature. In the Heart Outcomes Prevention Evaluation (HOPE) study population, only hs-CRP levels >6 mg/L were found to be predictive of adverse cardiovascular events (OR 1.26, 95% CI 1.01 to 1.56, p = 0.04).¹⁶ In the large prospective AtheroGene study, the OR of hs-CRP as a predictor of adverse cardiovascular events was 2.4 (95% confidence interval 1.1 to 4.6, p = 0.027), less than that of other acute-phase reactants.¹⁷ In the prospective Atherosclerosis Risk in Communities Study, most novel risk markers, including hs-CRP, did not significantly increase prediction of CAD events. However, traditional risk factors predicted CAD events with an area under the receiver-operating characteristic curve of approximately 0.8.¹⁰ These observations collectively suggest that a high hs-CRP level is in large part attributable to the presence of conventional risk factors, thus limiting its value as a risk factor over and above known CAD risk factors in multivariate risk models.¹⁸

IL-6 and TNF-α are the main inducers of hepatic acute-phase proteins, including CRP.¹⁹ Levels of these cytokines in serum correlate with various risk factors for CAD such as obesity, insulin resistance, diabetes mellitus, hypertension, smoking, and hyperlipidemia.¹⁰ Pai et al⁹ reported that IL-6 and soluble TNF-α receptors 1 and 2 were associated with increased risk of CAD on univariate analysis, but after adjustment for lipid and nonlipid factors, this association was no longer significant. This observation suggests that, like hs-CRP, the association of IL-6 and TNF-α with increased risk for CAD is mainly due to their association with traditional risk factors. This implies that measurement of these markers of inflammation provides at best a minor incremental value in assessing CAD risk.

It has been suggested that inflammation may be a response to vascular injury caused by shear stress, oxidized lipids, smoking, and high levels of advanced glycation end products.²⁰ The univariate association between hs-CRP and cardiovascular events can therefore be explained by the presence of conventional risk factors that are often present in patients with CAD.¹⁰ hs-CRP levels also correlate significantly with the Framingham risk score.²¹

Some investigators have attempted to correlate hs-CRP levels with atherosclerotic burden but have found no or a poor correlation between blood levels of this protein with coronary artery calcium, aortic plaque, or extent of CAD after adjustment for traditional risk factors.²², ²³, ²⁴, ²⁵, ²⁶ In the Framingham Heart Study population, there was a significant correlation between hs-CRP and coronary artery calcium, but after adjustment for age, Framingham risk score, and body mass index, the correlation remained significant only in men and that, too, was very weak (r = 0.19, p <0.05).²⁷ Zebrack et al²⁸ reported that hs-CRP levels correlated with extent of CAD on angiography, but the correlation coefficients were very low (0.02 to 0.08). Although others have reported higher levels of hs-CRP and IL-6 levels in serum in patients with CAD (vs those without CAD),²⁹, ³⁰ this relation was modest and not adjusted for risk factors. This is in concordance with the results of the present study. We found that serum levels of hs-CRP and IL-6 were associated with some indexes of CAD severity on coronary angiography in the unadjusted model, but after adjusting for risk factors, this association was lost.

We have focused this discussion primarily on hs-CRP levels, but data with measurement of IL-6, TNF-α, vascular adhesion molecules, and other inflammatory markers relating to extent of atherosclerosis or occurrence of events are even less significant.

The present study has 3 major strengths. First, it is a prospective study of consecutive unselected patients with cardiac chest pain. Second, we performed a very detailed and extensive analysis of coronary angiograms and even included nonobstructive lesions to detect any possible correlation with inflammatory markers. Third, unlike most previous studies, samples were not stored for long periods but were analyzed soon after the index hospitalization of each patient. Hence, technical issues, such as aliquoting of serum, repeated freezing, and thawing of blood samples, and the time delay between sampling and assay were avoided in our study.

Our study also has some limitations. First, coronary angiography detects only coronary luminal narrowing and not systemic atherosclerotic burden; the latter may affect serum levels of inflammatory markers. Second, hs-CRP, IL-6, and TNF-α were measured in peripheral blood; this does not elucidate the site of origin of inflammatory mediators. Third, the follow-up period in our study was relatively short, but it is well known that most patients hospitalized with chest pain who develop a cardiac event will do so in the next 6 months.

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