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Original Article

Elevated Circulating Levels of Tumor Necrosis Factor in Severe Chronic Heart Failure

List of authors.
  • Beth Levine, M.D.,
  • Jill Kalman, M.D.,
  • Lloyd Mayer, M.D.,
  • Howard M. Fillit, M.D.,
  • and Milton Packer, M.D.

Abstract

Background and Methods.

Although cachexia often accompanies advanced heart failure, little is known about the causes of the cachectic state. To assess the potential role of tumor necrosis factor in the pathogenesis of cardiac cachexia, we measured serum levels of the factor in 33 patients with chronic heart failure, 33 age-matched healthy controls, and 9 patients with chronic renal failure.

Results.

Mean (±SEM) serum levels of tumor necrosis factor were higher in the patients with heart failure (115±25 U per milliliter) than in the healthy controls (9±3 U per milliliter; P<0.001). Nineteen of the patients with chronic heart failure had serum levels of tumor necrosis factor ≥39 U per milliliter (>2 SD above the mean value for the control group), whereas the remaining 14 patients had serum levels of tumor necrosis factor below this level. The patients with high levels of tumor necrosis factor were more cachectic than those with low levels (82±3 vs. 95±6 percent of ideal body weight, respectively; P<0.05) and had more advanced heart failure, as evidenced by their higher values for plasma renin activity (2.92±0.53 vs. 1.06±0.53 ng per liter per second [10.5±1.9 vs. 3.8±1.9 ng per milliliter per hour]; P<0.01) and lower serum sodium concentration (135±1 vs. 138±1 mmol per liter; P<0.05). The group with high levels of tumor necrosis factor also had lower hemoglobin levels (7.82±0.2 vs. 8.69±0.4 mmol per liter [12.6±0.4 vs. 14.0±0.6 g per deciliter]) and higher values for blood urea nitrogen (19.5±2.2 vs. 12.5±1.8 mmol per liter) than the group with low levels of tumor necrosis factor (P<0.05 for both). The high levels of tumor necrosis factor were not due solely to decreased renal clearance, however, since the levels in the patients with heart failure were considerably higher than those in the nine patients with chronic renal failure (115±25 vs. 45±25 U per milliliter; P<0.05).

Conclusions.

These findings indicate that circulating levels of tumor necrosis factor are increased in cachectic patients with chronic heart failure and that this elevation is associated with the marked activation of the renin—angiotensin system seen in patients with end-stage cardiac disease. (N Engl J Med 1990; 323:236–41.)

Introduction

SINCE the time of Hippocrates, cachexia has been recognized as a prominent feature of patients with end-stage heart failure.1 , 2 Although numerous theories about its pathogenesis have been proposed,2 , 3 the cause of the profound weight loss and anorexia in these patients remains unclear. Some investigators have suggested that the weight loss is related to a reduction in caloric intake, the malabsorption of nutrients from an edematous bowel, or an impairment of oxygen delivery to the tissues.3 , 4 These three factors, however, should act to reduce the total energy consumption of the body, yet patients with heart failure characteristically have an increased basal metabolic rate.5 Other reports have postulated that in patients with heart failure the catabolism of adipose tissue and skeletal muscle is accelerated to meet the increased metabolic demands of the heart and respiratory muscles,3 , 5 but there is no direct evidence to support this hypothesis. Finally, some studies have proposed that cachexia may be mediated by the enhanced secretion of an endogenous hormone with antianabolic and catabolic properties.3 Patients with heart failure, however, have not yet been shown to produce excessive amounts of any specific substance capable of causing weight loss and anorexia.

Tumor necrosis factor (cachectin) is a pluripotent cytokine produced primarily by monocytes that has been shown experimentally to cause fever and hypotension (during short-term administration) and cachexia and anorexia (during long-term administration).6 7 8 Elevated circulating levels of tumor necrosis factor have been noted in patients with a variety of neoplastic, infectious, and collagen vascular disorders,9 10 11 12 13 14 15 16 17 many of which are characterized by severe weight loss and anorexia. Interestingly, circulating levels of tumor necrosis factor have not been measured in patients with congestive heart failure, even though the degree of cachexia in this disorder closely mimics that seen in patients with cancer.2 The present study was designed to assess the potential role of tumor necrosis factor in this cardiovascular disorder.

Methods

Patient Population

Thirty-three patients with congestive heart failure and 33 healthy, age-matched controls composed our study population. The heart-failure cohort consisted of 24 men and 9 women, 42 to 83 years of age (mean, 62). All had dyspnea or fatigue at rest or on modest exertion (New York Heart Association functional Class III or IV) and a left ventricular ejection fraction (as measured by radionuclide ventriculography) of less than 35 percent. The cause of heart failure was coronary artery disease in 19 patients and primary dilated cardiomyopathy in 14 patients. All patients were clinically stable at the time of evaluation and had no evidence of active infection, inflammatory disease, or cancer. The control cohort consisted of 21 men and 12 women, 40 to 82 years of age (mean, 61); none had any acute or chronic illness or reported any symptoms related to the cardiovascular system.

Study Design

The patients with heart failure were each admitted to a clinical research unit for five days, during which they consumed a daily diet containing 86 mmol of sodium (with free access to water) and received constant doses of digoxin and diuretic agents but no vasodilator drugs. The doses of diuretic agents had been previously titrated so that there was no evidence of edema on physical examination; no patient had received a converting-enzyme inhibitor or an anti-inflammatory drug within the preceding two weeks. At the end of the five-day observation period, blood was collected (after the patient had remained supine for at least 60 minutes in a quiet room) for the measurement of hemoglobin, hematocrit, serum electrolytes, blood urea nitrogen, serum creatinine, plasma renin activity, plasma norepinephrine, and serum tumor necrosis factor. All blood samples collected for the analysis of circulating hormones and cytokines were stored at -20°C until the time of assay. Right-sided heart catheterization and arterial cannulation were performed in all patients for the measurement of intracardiac and systemic pressures, respectively, with the use of procedures described elsewhere.18 All hemodynamic determinations were carried out 12 to 24 hours after catheterization to allow the dissipation of hemodynamic changes related to the intravascular instrumentation.

Hormone and Cytokine Assays

Plasma renin activity and plasma norepinephrine levels were measured by radioimmunoassay19 and high-performance liquid chromatography,20 respectively.

The activity of tumor necrosis factor was measured by a modification of the method described by Ruff and Gilford.21 L929 cells (courtesy of Dr. A. Cerami, Rockefeller University, New York) were seeded at a density of 4.5×104 in 96-well flat-bottom plates (Linbro, Oxnard, Calif.) and cultured in Minimal Essential Medium (Gibco, Grand Island, N.Y.) containing 5 percent fetal-calf serum (Gibco) and 1 percent penicillin-streptomycin (Gibco). Ten-microliter serum samples and standards of recombinant tumor necrosis factor (Cetus, Emeryville, Calif.) were added in duplicate to the L929-cell culture and incubated in the presence of 1 μg of actinomycin D per milliliter of culture (Sigma, St. Louis) for 12 to 18 hours. Standards of recombinant tumor necrosis factor were included in each 96-well microliter plate. To determine whether L929 cytotoxicity was due to tumor necrosis factor alpha, all samples were incubated in both the presence and the absence of 10 μl of rabbit anti-tumor necrosis factor alpha serum (Cetus) capable of neutralizing 4×103 U of tumor necrosis factor per milliliter; the addition of the antiserum caused more than 80 percent inhibition of observed cytotoxicity in the samples with elevated tumor necrosis factor activity. The assays were performed without the investigators' knowledge of the clinical or hormonal status of either patients or controls.

L929 cytotoxicity was determined with a colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay.22 Ten microliters of fresh MTT solution was added to each microwell, and the plates were incubated at 37°C for four hours. Acid-isopropanol (100 μl) and distilled water (100 μl) were then added to each well, and the plates were read on a Microelisa automated reader (Physica, New York) with a test wavelength of 570 mm and a reference wavelength of 630 mm. The activity of tumor necrosis factor was determined by a modified probit analysis.23 The interassay variation for repeated determinations of tumor necrosis factor was within 10 to 15 percent.

Data Analysis

Patients were considered cachectic if their weight was less than 85 percent of the predicted ideal body weight as compared with controls matched for age, sex, and height who were enrolled in the Health and Nutrition Examination Survey.24 This definition has been used in previous studies of malnutrition and cachexia in cardiac and noncardiac disorders.25 26 27 Historical estimates of weight loss are unreliable in patients with congestive heart failure, because the weight loss related to cachexia may be obscured by the weight gain related to fluid retention.

The patients with heart failure were divided into two groups on the basis of their serum levels of tumor necrosis factor. The group with high levels of tumor necrosis factor consisted of patients in whom the levels exceeded (by more than 2 SD) the mean level seen in the control group (i.e., levels ≥39 U per milliliter). Patients whose levels of tumor necrosis factor were below 39 U per milliliter composed the group with low levels of tumor necrosis factor. The significance of the differences between the two groups was evaluated by the t-test for independent data (in the case of quantitative variables) and by Fisher's exact test (in the case of qualitative variables). All P values are two-tailed; all group data are expressed as means ±SEM.

Results

Figure 1. Figure 1. Serum Levels of Tumor Necrosis Factor in 33 Patients with Chronic Heart Failure (CHF), 9 Patients with Chronic Renal Failure (CRF), and 33 Healthy, Age-Matched Controls.

The 33 patients with heart failure had higher mean serum levels of tumor necrosis factor (115±25 U per milliliter) than the 33 controls (9±3 U per milliliter; P<0.001) (Fig. 1). Serum levels of tumor necrosis factor were not elevated in all patients with heart failure, however. Nineteen patients had serum levels of tumor necrosis factor ≥39 U per milliliter (>2 SD above the mean value for the control group), whereas 14 patients had serum levels of tumor necrosis factor <39 U per milliliter.

Table 1. Table 1. Demographic, Hemodynamic, and Biochemical Characteristics of 33 Patients with Heart Failure, According to Serum Level of Tumor Necrosis Factor.* Figure 2. Figure 2. Relation between Serum Levels of Tumor Necrosis Factor and Plasma Renin Activity in Patients with Chronic Heart Failure.

Solid symbols denote patients with normal serum sodium concentrations (≥137 mmol per liter), open symbols patients with hyponatremia, triangles patients with cachexia (<85 percent of ideal body weight), and circles patients without cachexia. There was a close association among cachexia, hyponatremia, and high levels of circulating tumor necrosis factor and renin activity. To convert nanograms per milliliter per hour to nanograms per liter per second, multiply by 0.2778.

The two groups were similar with respect to age, sex, cause of heart failure, left ventricular ejection fraction, dose of furosemide, and all hemodynamic variables (Table 1). The patients with high levels of tumor necrosis factor, however, had more marked activation of the renin—angiotensin system than the patients with low levels, as indicated by their higher values for plasma renin activity (2.92±0.53 vs. 1.06±0.53 ng per liter per second [10.5±1.9 vs. 3.8±1.9 ng per milliliter per hour]; P<0.01) and lower values for serum sodium concentration (135±1 vs. 138±1 mmol per liter; P<0.05). Seven of the nine patients with plasma renin activity below 0.56 ng per liter per second (2 ng per milliliter per hour) had serum levels of tumor necrosis factor under 39 U per milliliter; in contrast, 13 of the 16 patients with plasma renin activity above 1.39 ng per liter per second (5 ng per milliliter per hour) had serum levels of tumor necrosis factor above 39 U per milliliter (P<0.02 for the comparison between groups) (Fig. 2). Similarly, hyponatremia (as defined by a serum sodium concentration below 137 mmol per liter) was present in 13 of the 19 patients with high levels of tumor necrosis factor but in only 5 of the 14 patients with low levels. The activity of the sympathetic nervous system (as assessed by plasma norepinephrine levels) did not differ between the two groups.

Body weight in our 33 patients with heart failure ranged from 51 to 144 percent of ideal weight. The weights in the group with low levels of tumor necrosis factor were similar (95±6 percent of ideal body weight) to those predicted for a cohort matched for age, sex, and height; in contrast, the weights of the patients with high levels of tumor necrosis factor were significantly lower (82±3 percent of ideal body weight; P<0.05 for the comparisons with both the control cohort and the group with low levels of tumor necrosis factor). Fourteen of the 19 patients (73 percent) in the group with high levels of tumor necrosis factor but only 5 of 14 patients (36 percent) in the group with low levels were cachectic (body weight <85 percent of ideal).22 23 24 There was also a close relation between low body weight and the activation of the renin—angiotensin system. Plasma renin activity was significantly higher (2.97±0.53 vs. 1.00±0.28 ng per liter per second [10.7±1.9 vs. 3.6±1.0 ng per milliliter per hour]; P<0.01) and the serum sodium concentration significantly lower (135±1 vs. 139±1 mmol per liter; P<0.005) in the patients with cachexia than in those who were not cachectic. Hyponatremia was present in 14 of the 19 patients with cachexia but in only 4 of the 14 patients without cachexia (P<0.05).

The patients with high levels of tumor necrosis factor had lower values for hemoglobin (7.82±0.2 vs. 8.69±0.4 mmol per liter [12.6±0.4 vs. 14.0±0.6 g per deciliter]; P<0.05) and hematocrit (38.6±1.2 vs. 43.3±1.7 percent; P<0.05) and higher values for blood urea nitrogen (19.5±2.2 vs. 12.5±1.8 mmol per liter; P<0.05) and serum creatinine (149±14 vs. 104±4 μmol per liter; P<0.02) than the patients with low levels of tumor necrosis factor (Table 1), but the values for the factor were not related to creatinine clearance in the 12 patients in whom both variables were measured (r = -0.32). To gain further assurance that the high levels of tumor necrosis factor were not due to reduced renal clearance, we measured the levels of tumor necrosis factor in nine patients with chronic renal failure (mean serum creatinine concentration, 845±80 μmol per liter). The level of tumor necrosis factor (45±25 U per milliliter) was significantly lower (P<0.05) than that of the patients with chronic heart failure (115±25 U per milliliter) but only somewhat higher (P not significant) than that of the healthy controls (9±3 U per milliliter).

To determine the effects of diuresis on values for tumor necrosis factor, we measured serum levels of tumor necrosis factor before and after one to two weeks of treatment with intravenous furosemide in 10 additional patients with chronic heart failure. Despite a fall in weight from 82.2±6.0 to 76.7±5.9 kg (P<0.005), the mean levels of tumor necrosis factor in these patients declined slightly but not significantly (73±23 to 48±17 U per milliliter), and the levels before and after diuresis were significantly correlated in individual patients (r = 0.77).

Discussion

The findings of this study indicate that circulating levels of tumor necrosis factor are increased in patients with chronic heart failure. Serum levels of the cytokine were elevated primarily in the patients with the most advanced disease (as indicated by activation of the renin—angiotensin system) and with the stigmata of chronic illness (cachexia and anemia). Increased circulating levels of tumor necrosis factor have been noted in patients with a variety of neoplastic, infectious, and collagen vascular disorders9 10 11 12 13 14 15 16 17; in many of these reports, high levels of tumor necrosis factor identified the patients who were the most severely affected and the least likely to survive.9 , 10 , 14 , 17 Similarly, in this study, levels of tumor necrosis factor were principally elevated in patients with chronic heart failure who had high plasma renin activity, low serum sodium concentrations, and poor renal function — the most important determinants of mortality in Class III and IV heart failure.28 29 30 Levels of tumor necrosis factor were not related to cardiac output or ventricular filling pressure, probably because measures of left ventricular performance lose their prognostic importance as patients enter the terminal stages of their disease.28 , 31 This study demonstrates that circulating levels of tumor necrosis factor may be increased and have clinical importance in diseases that are neither neoplastic nor inflammatory.

Did the elevated levels of tumor necrosis factor in our patients with heart failure exert physiologic effects? Despite similar heights, the patients with high levels of tumor necrosis factor were more likely to have low body weights than those with low levels. This difference in weight could not be explained by differences in the degree of hydration, since the two groups were treated with similar doses of diuretic agents and had similar right and left ventricular filling pressures; in addition, decreases in weight produced by diuretic agents did not increase serum levels of tumor necrosis factor in our study. Hence, the low body weight in our patients with high levels of tumor necrosis factor probably indicated the presence of cachexia. Weight loss is an established effect of the administration of tumor necrosis factor to laboratory animals,8 , 32 and tumor necrosis factor has been implicated in the development of cachexia in patients with cancer or chronic infections.7 , 8 This malnutrition may be related to an anorectic action of tumor necrosis factor,33 caused either directly by the cytokine or by its ability to stimulate the production of interleukin-1.33 , 34 In addition, tumor necrosis factor suppresses the expression of several genes that encode for essential lipogenic enzymes and promotes the breakdown of adipose tissue and skeletal muscle.8 , 35 36 37 38 39 The finding of low body weight in our patients with high levels of tumor necrosis factor is particularly striking, since these patients had marked activation of the renin—angiotensin system (as evidenced by high plasma renin activity and low serum sodium concentrations28 , 40); such activation would have been expected to cause sodium retention and weight gain rather than weight loss. Yet our finding of a close association between cachexia and hyponatremia is consistent with previous studies, which have shown that both skin-fold thickness27 (a measure of total body fat) and total exchangeable potassium (a measure of lean body mass) are reduced in hyponatremic patients with heart failure.41 , 42

Cytokines have been shown to produce anemia under experimental conditions,8 and they may contribute to the pathogenesis of the hypoplastic anemia seen in patients with chronic infections.43 Our finding that patients with high levels of tumor necrosis factor had lower values for hemoglobin and hematocrit than those with low levels suggests that tumor necrosis factor may also explain the low red-cell counts seen in patients with cardiac cachexia.2 The anemia may be caused by a nutritional deficiency related to the anorectic effect of the cytokine8 , 33; in addition, tumor necrosis factor appears to inhibit the proliferation and differentiation of hematopoietic cells.43 , 44 Any possible relation between tumor necrosis factor and the anemia seen in cardiac cachexia, however, should be considered uncertain at the present time, since the activation of the renin—angiotensin system seen in patients with high levels of tumor necrosis factor could cause sodium retention and a decline in red-cell counts as a result of hemodilution. We attempted to address this factor in the present study by titrating the doses of diuretic agents to eliminate any clinically apparent fluid retention. This approach has been shown to minimize the difference in the total level of sodium in the body between patients with heart failure and high levels of renin and those with heart failure and low levels of renin42; in fact, cardiac filling pressures were similar in the two groups. This finding suggests that the low red-cell counts found in our patients with high levels of tumor necrosis factor were not the result of hemodilution.

The patients with elevated circulating levels of tumor necrosis factor in our study had greater impairment of renal function than the patients with low levels of the factor. This observation has three possible explanations. First, the renal insufficiency in patients with high levels of tumor necrosis factor may be an indication of the advanced severity of heart failure in this group; renal perfusion and function are both characteristically depressed in patients with heart failure who have high levels of renin.40 , 45 Second, the renal dysfunction observed in our patients with high levels of tumor necrosis factor may have been related to a direct toxic effect of the cytokine on the kidneys. Tumor necrosis factor is concentrated in the kidneys,46 where it has been shown to cause deleterious structural and functional changes in both laboratory animals and humans.47 48 49 50 Third, since the kidneys appear to be the primary site of the catabolism of tumor necrosis factor,51 any impairment of renal function could contribute to, rather than result from, the elevation of serum levels of tumor necrosis factor. These levels were not correlated with creatinine clearance, however, and the patients with chronic heart failure had higher levels of tumor necrosis factor than those with chronic renal failure. These observations suggest that the elevated concentration of tumor necrosis factor seen in some patients with heart failure is related to enhanced production of the cytokine rather than reduced clearance.

What factors could promote the synthesis of tumor necrosis factor in patients with end-stage heart failure? As the severity of heart failure worsens and renal blood flow declines, the kidney releases both renin and prostaglandins (particularly prostaglandin E2) into the circulation, and they interact to regulate glomerular filtration and systemic vascular resistance.40 , 52 Hyponatremia is the principal clinical marker for the enhanced release of these two hormones,40 and it was also present in the patients with heart failure in our study who had elevated serum levels of tumor necrosis factor. Interestingly, concentrations of prostaglandin E2 equivalent to those measured in the plasma of patients with hyponatremic heart failure have been shown to stimulate the production of tumor necrosis factor from monocytes in vitro.40 , 53 This stimulatory effect of physiologic concentrations of prostaglandin E2 on resting monocytes should be distinguished from the inhibitory effect that pharmacologic concentrations of prostaglandin E2 have on the production of tumor necrosis factor by monocytes that have been activated by endotoxin.54 Further studies are needed to confirm or refute this hypothesis and elucidate the importance of additional stimuli.

The findings of the present study should be interpreted cautiously. We measured circulating levels of tumor necrosis factor using a bioassay based on the ability of the cytokine to induce cytotoxicity in vitro. Cytotoxicity assays, although more variable than immunoassays, ensure that the cytokine measured is biologically active, whereas immunoassays may recognize inactive, denatured, aggregated, or fragmented molecules of tumor necrosis factor.55 , 56 Other cytokines can exert cytotoxic effects in this assay,55 but we attempted to minimize such interpretive difficulties by inhibiting the cytotoxicity that we observed with antiserum to tumor necrosis factor alpha. Yet our findings do not rule out an important role in heart failure for other cytokines, specifically interleukin-1, the production of which is stimulated by tumor necrosis factor34 and with which tumor necrosis factor shares several biologic actions.57 Furthermore, we measured serum levels of tumor necrosis factor at only one time, but the factor has a very short half-life in the bloodstream,46 , 50 and its biologic effects may be related more to the duration of exposure to the cytokine than to its absolute level in the circulation.32 To address this issue, future studies will need to measure sequentially not only the levels of circulating tumor necrosis factor but also its production by monocytes at various stages of the disease. These assessments, when correlated with hemodynamic, hormonal, and clinical variables, may provide important insight into the actions of tumor necrosis factor in chronic heart failure.

Funding and Disclosures

Supported by grants (RO1-HL-25055, KO4-HL-01229, RO1–CA41583, RO1–AI23504, PO1–AI24671, and MO1-RR-00071) from the National Institutes of Health. Dr. Packer is the recipient of a Research Career Development Award from the National Heart, Lung, and Blood Institute. Dr. Mayer is the recipient of a Career Development Award from the Irma T. Hirschl Trust, New York.

We are indebted to Dr. Gerald W. Neuberg, Dr. Marrick L. Kukin, and Dr. Joshua Penn for conducting the clinical research protocols; to Ms. Norma Medina, R.N., and Ms. Madeline Yushak, R.N., for performing the hemodynamic measurements; to Dr. Kirk Sperber for assistance in the assay for tumor necrosis factor; and to Dr. Anthony Cerami for supplying the L929 cells.

Author Affiliations

From the Divisions of Cardiology (J.K., M.P.) and Clinical Immunology (B.L., L.M.), Department of Medicine, and the Department of Geriatrics (H.M.S.), Mount Sinai School of Medicine, City University of New York. Address reprint requests to Dr. Packer at the Division of Cardiology, Mount Sinai School of Medicine, 1 Gustave Levy Pl., New York, NY 10029.

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    Figures/Media

    1. Figure 1. Serum Levels of Tumor Necrosis Factor in 33 Patients with Chronic Heart Failure (CHF), 9 Patients with Chronic Renal Failure (CRF), and 33 Healthy, Age-Matched Controls.
      Figure 1. Serum Levels of Tumor Necrosis Factor in 33 Patients with Chronic Heart Failure (CHF), 9 Patients with Chronic Renal Failure (CRF), and 33 Healthy, Age-Matched Controls.
    2. Table 1. Demographic, Hemodynamic, and Biochemical Characteristics of 33 Patients with Heart Failure, According to Serum Level of Tumor Necrosis Factor.*
      Table 1. Demographic, Hemodynamic, and Biochemical Characteristics of 33 Patients with Heart Failure, According to Serum Level of Tumor Necrosis Factor.*
    3. Figure 2. Relation between Serum Levels of Tumor Necrosis Factor and Plasma Renin Activity in Patients with Chronic Heart Failure.
      Figure 2. Relation between Serum Levels of Tumor Necrosis Factor and Plasma Renin Activity in Patients with Chronic Heart Failure.

      Solid symbols denote patients with normal serum sodium concentrations (≥137 mmol per liter), open symbols patients with hyponatremia, triangles patients with cachexia (<85 percent of ideal body weight), and circles patients without cachexia. There was a close association among cachexia, hyponatremia, and high levels of circulating tumor necrosis factor and renin activity. To convert nanograms per milliliter per hour to nanograms per liter per second, multiply by 0.2778.

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