(Circulation. 2001;103:2055.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Cytokines and Cytokine Receptors in Advanced Heart Failure
An Analysis of the Cytokine Database from the Vesnarinone Trial (VEST)
From the Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Tex (A.D., D.L.M.); the Veterans Affairs Health Services Research and Development Center of Excellence, Houston, Tex (N.J.P.); the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (A.M.F.); the Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cleveland, Ohio (J.B.Y.); and Clinical Cardiovascular Research, Gaithersburg, Md (B.G.W.).
Correspondence and reprint requests to Douglas L. Mann, MD, Cardiology Research (151C), Houston VAMC, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu
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Abstract |
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Background—Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure.
Methods and
Results—We analyzed circulating levels
of cytokines (tumor necrosis factor [TNF] and interleukin-6)
and their cognate receptors in 1200 consecutive patients who were
enrolled in a multicenter clinical trial of patients with advanced
heart failure. This analysis constitutes the largest
analysis of cytokines and cytokine receptors to
date. Analysis of the patients receiving placebo showed that
increasing circulating levels of TNF, interleukin-6, and the soluble
TNF receptors were associated with increased mortality. In men, there
was a linear increase in circulating levels of TNF with advancing age.
Women 
50 years of age had relatively low levels of TNF, but TNF
levels were disproportionately higher in women >50 years of
age. No differences existed in cytokines and/or
cytokine receptors in whites versus nonwhites, and circulating
levels of cytokines and cytokine receptors were
significantly greater in patients with ischemic heart
disease.
Conclusions—Cytokines and cytokine receptors are independent predictors of mortality in patients with advanced heart failure. Moreover, circulating levels of cytokines are modified by age, sex, and cause of heart failure.
Key Words: heart failure • cytokines • tumor necrosis factor
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Introduction |
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Since the original observation that circulating levels of tumor necrosis factor (TNF) were elevated in patients with heart failure, there have been countless reports in which elevated levels of proinflammatory cytokines and/or their cytokine receptors have been observed in patients with heart failure.1 Thus far, prior studies have shown that circulating levels of TNF and interleukin-6 (IL-6) are elevated in direct relation to deteriorating functional class of heart failure.2 3 4 Moreover, previous reports have suggested that elevated levels of cytokines and cytokine receptors predict a worse clinical outcome in patients with heart failure.2 5 6 7 8 However, the clinical significance of these studies is uncertain for 2 reasons. (1) They were performed in small numbers of patients, and (2) many of the studies were performed in a single center, in which systematic referral bias is perhaps unavoidable. In addition to the above limitations, no previous study has had sufficient size to address a number of important issues relating to the elaboration of cytokines and cytokine receptors in heart failure, including the influence of age, sex, race, and cause of heart failure on cytokines and cytokine receptors.
To address the limitations of the above studies, we performed a systematic analysis of cytokines and their cognate cytokine receptors in a large-scale, multicenter, clinical trial in patients with advanced heart failure: the Vesnarinone trial (VEST).9 The present analysis, which was performed in 1200 consecutive patients with advanced heart failure, constitutes the largest analysis of cytokines and cytokine receptors that has been performed to date.
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Methods |
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Patient Population
The patient population consisted of the first consecutive 1200 patients enrolled in VEST.9 The patient population was drawn from 189 different clinical sites in North America. A total of 31 patients were excluded from the final data analysis because of protocol violations (18 patients were in New York Heart Association [NYHA] class II at the time of enrollment, and 13 had inadequate baseline blood samples). Thus, the final patient cohort consisted of 1169 patients.
Circulating Levels of Cytokines and
Cytokine Receptors
Circulating levels of TNF, IL-6, soluble TNF receptor
1 (sTNFR1), soluble TNF receptor 2 (sTNFR2), and soluble IL-6 receptor
(sIL-6R) were measured at baseline before randomization into VEST. If
the patient had a recent infection, the cytokine and
cytokine receptors were drawn 2 weeks after the resolution of
the most recent infection. All patients were on stable doses of ACE
inhibitors, diuretics, digoxin, and/or vasodilators
for 30 days before obtaining baseline measurements. Circulating levels
of cytokines and cytokine receptors were measured using
an ELISA (R&D Systems) that measures "total" TNF and IL-6
(ie, free [unbound] cytokine and cytokine bound to
receptors; see Data Supplement for details). After completing the
cytokine analysis, the relevant demographic and
clinical data corresponding to these samples were obtained from the
VEST Data Coordinating Center at the University of Wisconsin in
Madison, Wisconsin.
Statistical Analysis
All data are presented as mean±SEM. Because
the cytokine data were not normally distributed, data were
subjected to logarithmic transformation before all statistical
analyses. However, to permit comparison with results from other
studies, the cytokine data are presented as the
mean±SEM of the untransformed data. Student’s
t test was used to test for
differences in continuous variables, and the
2 test was used for categorical
variables. Tests for differences in cytokine levels by race
were performed using ANOVA. Correlations of cytokine levels
with demographic characteristics were performed using Pearson’s
product-moment correlations. ANCOVA was used to correct for
differences in baseline characteristics and to evaluate differences in
levels of cytokines and receptors between certain subgroups.
Survival curves for cytokine groups were calculated by the
Kaplan-Meier method, and survival among groups was compared using the
log-rank test. The prognostic value of increased cytokine and
cytokine receptor levels was examined using a Cox
proportional-hazards model (SAS for Windows, version 6.12). Significant
differences were said to exist at
P<0.05 for all
parameters except for correlations, which were considered
to be significant at P<0.01
due to multiple comparisons.
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Results |
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Baseline Characteristics of the Study Population
As shown in Table 1
the age, left ventricular ejection
fraction, serum sodium, body weight, and Minnesota living with heart
failure scores were significantly different in the patients with NYHA
class III and IV heart failure, reflecting the greater degree of
disease severity in the patients with class IV heart failure. The
demographic and biochemical characteristics of the patients enrolled in
the cytokine analysis of VEST were similar to the data
reported for the overall cohort of patients enrolled in
VEST.9
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Circulating Levels of Cytokines and
Cytokine Receptors in Heart Failure
The baseline levels of sTNFR1, sTNFR2, and IL-6 were
significantly greater in the patients with class IV heart failure when
compared with class III heart failure patients, but no significant
differences existed in the plasma TNF levels in patients with NYHA
class III and IV heart failure (Data Supplement).
Figure 1 illustrates the distribution of circulating TNF and
IL-6 levels as a function of NYHA functional class. The important
finding illustrated by these figures is that there was a great deal of
overlap of both TNF and IL-6 levels in patients with NYHA class III and
IV heart failure, suggesting that the elaboration of proinflammatory
cytokines is not strictly confined to patients with end-stage
heart failure.
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Relationship Between Cytokines,
Cytokine Receptors, and Patient Characteristics
As shown in
Table 2, a significant positive correlation existed between
patient age and circulating levels of TNF, IL-6, sTNFR1, and sTNFR2.
Table 3 compares and contrasts the circulating levels of
TNF and IL-6 in men and women. Although the mean TNF level was not
significantly different in men and women, a small but significant
increase existed in the mean level of IL-6 in men. To determine whether
there was an interaction between age and sex, we examined the
relationship between age and circulating levels of TNF in men and
women. The salient finding shown by
Figure 2 is that TNF levels increased linearly with age in
men, whereas women had a dichotomous relationship: TNF levels remained
relatively flat in women until 
50 years of age, and after 50 years
of age, TNF levels sharply increased. Moreover, the levels of TNF in
women after age 50 were relatively greater than the levels observed in
men up until 70 years of age, at which time the circulating levels of
TNF became similar in the 2 groups. This significant interaction
(P<0.05) between patient sex
and age was not observed for IL-6, sTNFR1, sTNFR2, or sIL-6R (data not
shown).
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Table 3
shows that the levels of TNF and IL-6 were
significantly increased in patients with ischemic heart
disease. Similarly, levels of sTNFR1, sTNFR2, and sIL-6R were also
significantly higher in patients with ischemic heart disease
when compared with those in patients with dilated
cardiomyopathy (data not shown). These differences
persisted even after correcting for baseline characteristics including
age, sex, NYHA class of heart failure, ejection fraction, and serum
sodium. We also examined circulating levels of TNF and IL-6 as a
function of race (white, black, and Hispanic), smoking status, and
history of alcohol consumption.
Table 3 shows that no significant difference existed in
either TNF or IL-6 levels for any of these subgroups of
patients.
Relationship Between Cytokines,
Cytokine Receptors, and Mortality
To determine whether circulating levels of
cytokines and/or cytokine receptors predicted adverse
outcomes, we examined the relationship between cytokines and/or
cytokine receptors and patient mortality in the group of
patients who received placebo (NYHA class III, 352 patients; NYHA class
IV, 32 patients). The baseline clinical characteristics of the placebo
group were similar to the patients who received active therapy (data
not shown). At the end of the follow-up period (mean duration, 55
weeks; maximum duration, 78 weeks), 65 patients (16.9%) died and 319
patients (83.1%) were alive. As shown in
Table 4, the baseline levels of TNF, IL-6, sTNFR1, and
sTNFR2 were significantly higher in the group of patients who died
during follow-up, whereas the circulating levels of sIL-6R were not
significantly different in survivors and nonsurvivors.
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We next asked whether mortality increased as a function of
increasing levels of cytokines and/or cytokine
receptors.
Figure 3A shows that a significant overall difference
existed in survival as a function of increasing TNF levels
(P<0.007 by log-rank test),
with the worst survival in patients who had TNF levels >75th
percentile. Similar findings were observed with respect to the
Kaplan-Meier analysis of circulating levels of IL-6 and sTNFR1,
which showed that a significant overall difference existed in survival
as a function of increasing levels of IL-6
(Figure 3B; P=0.007)
and sTNFR1
(Figure 3C;
P=0.0001), with the worst
survival observed for circulating levels of IL-6 and sTNFR1 that were
>75th percentile. As shown in
Figure 3D, survival also decreased with increasing levels of
sTNFR2
(Figure 3D;
P=0.0001), with the worst
survival for circulating levels of sTNFR2 >50th percentile. A
univariate Cox analysis showed that TNF
(P=0.01), IL-6
(P=0.0003), sTNFR1
(P=0.0001), and sTNFR2
(P=0.0001) were significant
univariate predictors of mortality.
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We then entered each cytokine and/or cytokine receptor separately into a multivariate Cox proportional hazards model that included age, sex, cause of heart failure, NYHA class, ejection fraction, and serum sodium; the analysis was then performed using a backward elimination procedure. TNF (P=0.02), IL-6 (0.002), sTNFR1 (P=0.0001), and sTNFR2 (P=0.0001) remained significant independent predictors of mortality; NYHA class and ejection fraction were also retained in the statistical model as independent predictors of mortality. When all the cytokines and receptors were entered into the model together, only sTNFR2 remained a significant predictor of mortality, along with NYHA class and ejection fraction (Data Supplement). Finally, no significant difference existed in any of these parameters in the patients who died of pump failure or sudden death (Data Supplement).
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Discussion |
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The results of the present study, in which we examined the levels of cytokines and cytokine receptors in a well-characterized database obtained from a large multicenter clinical trial, provide answers to several of the important questions that were raised at the outset of this study. With respect to the first question of whether circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure, the data (placebo group) suggest that circulating levels of TNF, IL-6, sTNFR1, and sTNFR2 are independent predictors of increased mortality in patients with advanced heart failure. This statement is supported by the following information.
First, the baseline levels of TNF, IL-6, sTNFR1, and sTNFR2
were significantly higher in the nonsurvivors than in the survivors
(Table 4). Interestingly, the circulating levels of TNF and
IL-6 were not different in the patients who died suddenly compared with
those patients who died from pump failure (Data Supplement). Second,
Kaplan-Meier analyses
(Figure 3) showed that patient survival decreased as a
function of increasing levels of cytokines and/or
cytokine receptors: indeed, circulating levels of TNF, IL-6,
sTNFR1, and sTNFR2 >75th percentile were associated with the worst
survival. In contrast, circulating levels of sIL-6R levels were not
significantly different in the survivors and nonsurvivors. Third, a
multivariate Cox proportional hazards model showed that
circulating levels of TNF, IL-6, sTNFR1 and sTNFR2 were significant
independent predictors of mortality. Thus, these findings are
consistent with several previous
studies.2 6 8
Interestingly, circulating levels of TNFR2 were the best
independent overall predictor of mortality when cytokines and
cytokine receptors were simultaneously entered into
the multivariate model. This latter finding is
consistent with a smaller study by Ferrari et
al,5 but differs from that of
Rauchhaus et al,8 who
reported that TNFR1 was the single best predictor of mortality in
patients with heart failure. Although the reasons for this discrepancy
are unknown, they may relate to differences in patient demographics
between the studies (eg, tertiary care referral center versus
multicenter clinical trial population). Given that circulating soluble
TNF receptors are thought to be biologically
inert,10 it is not clear
whether circulating levels of sTNFR2 represent an epiphenomenon
that is associated with, but not causally related to, worsening disease
severity. In this regard, it is interesting to note that circulating
levels of sTNFR2 are thought to reflect increased activity of
TNF-
–converting
enzyme,11 a membrane-bound
enzyme that cleaves both TNF and TNFR2 from cell surface membranes.
Importantly, TNF-–converting enzyme levels correlate with the
degree of LV systolic dysfunction in patients with dilated
cardiomyopathy.12
Thus, circulating levels of sTNFR2 may be a "surrogate marker" for
worsening LV function and/or LV remodeling and may thus predict
worsening outcomes. Alternatively, it is possible that circulating
levels of sTNFR2 are causally linked to adverse outcomes in heart
failure, insofar as sTNFR2 is thought to act as a "carrier protein"
that is capable of binding to TNF and then slowly releasing this
potentially toxic cytokine into the
circulation.13 However, it
should be noted that because patients enrolled in this study had
advanced heart failure, the prognostic significance of circulating
cytokines or their receptors in mild heart failure cannot be
assessed from this database.
With respect to the second set of questions regarding the
influence of age, sex, race, and cause of heart failure on
cytokines and cytokine receptors, the aggregate data
provide several new and important insights that are not available from
smaller data sets. For example, we observed that there was an important
interaction between age and sex in patients with heart failure.
Although we observed that there was an overall increase in the level of
circulating cytokines and cytokine receptors with
advancing age, as has been reported in aging subjects who are free of
cardiovascular
disease,14 the age-related
changes that were observed were different in men and women.
Although TNF levels increased linearly with age in men with heart
failure, TNF levels remained relatively flat in women until 50 years
of age, after which TNF levels in women abruptly increased. Although
the mechanism(s) for this finding is not known, it is tempting to
speculate that increased levels of estrogen in the women 50 years of
age (presumably premenopausal) may have suppressed circulating levels
of TNF. Indeed, several studies have demonstrated that estrogens
inhibit TNF production in a variety of different cell types,
including monocytes and
osteoblasts.15 Nonetheless,
these studies should be regarded as provisional given the relatively
small number of female patients in each age group.
A second finding that was not anticipated from the clinical
literature was that circulating levels of cytokines and
cytokine receptors were consistently higher in patients
with ischemic cardiomyopathy than in
patients with dilated cardiomyopathy
(Table 3). Importantly, these differences persisted even
after correcting for baseline characteristics between the 2 groups,
including, age, sex, NYHA class, ejection fraction, and serum sodium.
Because myocardial ischemia is a known trigger for myocardial
biosynthesis of TNF and IL-6, these observations raise the interesting
possibility that episodic bouts of myocardial ischemia may
contribute to the total cytokine burden in heart failure and
thus contribute to disease progression and worsening outcomes in
patients with ischemic cardiomyopathy.
Alternatively, the higher levels of cytokines may be reflective
of the generalized inflammatory process that has been observed in
atherosclerotic heart disease.
Given the recent interest in differences in heart failure
outcomes on the basis of
race,16 we were also
interested in determining whether there were potential differences in
cytokine and/or cytokine receptor levels in different
racial groups in VEST. There were no obvious differences in the levels
of cytokines
(Table 3) and/or cytokine receptors between whites,
blacks, and Hispanics. However, the data on cytokine levels in
Hispanics should be regarded as provisional, because levels were
obtained in only a limited number of Hispanic patients. Insofar as
there seem to be differences in the frequency of TNF polymorphisms
and cytokine responses in blacks and whites, this question
remains an important area of discovery for the
future.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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The current analysis of cytokines and cytokines receptors in this large multicenter clinical trial bears a striking resemblance to prior analyses of neurohormonal markers, which have also been shown to be independent predictors of increased mortality in patients with heart failure.17 Although elevated levels of circulating neurohormones were once considered epiphenomena that were not related to disease progression in heart failure,17 the results of numerous clinical trials, wherein neurohormonal systems have been systematically antagonized, suggests that circulating neurohormones may contribute to disease progression in heart failure by virtue of their toxic effects on the heart and the peripheral circulation. Thus, the results of the present study suggest that, analogous to the classical neurohormones, cytokines may also represent an important therapeutic target in patients with heart failure. Indeed, this question is currently being addressed in ongoing multicenter clinical trials.
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Acknowledgments |
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The authors gratefully acknowledge the indefatigable technical assistance of Dorellyn Lee-Jackson, Wendy Skinner, and Adrienne Chee. We also thank Dr Andrew I. Schafer for his past and present support and guidance. This research was supported by Otsuka America Pharmaceuticals, Inc. Dr Deswal is the recipient of a Clinical Research Career Development Award (CRCD No. 712B) from the Veterans Affairs Cooperative Studies Program.
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Footnotes |
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Data Supplement can be found at www.circulationaha.org
Guest Editor for this article was Peter P. Liu, MD, FRCPC, FACC, Toronto Hospital, Toronto, Ontario, Canada.
Received October 9, 2000; revision received January 8, 2001; accepted January 26, 2001.
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References |
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J. E. Toblli, A. Lombrana, P. Duarte, and F. Di Gennaro Intravenous Iron Reduces NT-Pro-Brain Natriuretic Peptide in Anemic Patients With Chronic Heart Failure and Renal Insufficiency J. Am. Coll. Cardiol., October 23, 2007; 50(17): 1657 - 1665. [Abstract] [Full Text] [PDF]
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N. A. Turner, R. S. Mughal, P. Warburton, D. J. O'Regan, S. G. Ball, and K. E. Porter Mechanism of TNF{alpha}-induced IL-1{alpha}, IL-1{beta} and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones Cardiovasc Res, October 1, 2007; 76(1): 81 - 90. [Abstract] [Full Text] [PDF]
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G. M. Felker, L. A. Allen, S. J. Pocock, L. K. Shaw, J. J.V. McMurray, M. A. Pfeffer, K. Swedberg, D. Wang, S. Yusuf, E. L. Michelson, et al. Red Cell Distribution Width as a Novel Prognostic Marker in Heart Failure: Data From the CHARM Program and the Duke Databank J. Am. Coll. Cardiol., July 3, 2007; 50(1): 40 - 47. [Abstract] [Full Text] [PDF]
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M. Schaufelberger, I. Ekman, E. Bjornsson, E. Kalaitzakis, and T. Ekman Intestinal paracellular permeability is not affected in chronic congestive heart failure Eur J Heart Fail, June 1, 2007; 9(6-7): 574 - 578. [Abstract] [Full Text] [PDF]
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A. Trikas, C. Antoniades, G. Latsios, K. Vasiliadou, I. Karamitros, D. Tousoulis, C. Tentolouris, and C. Stefanadis Long-term effects of levosimendan infusion on inflammatory processes and sFas in patients with severe heart failure Eur J Heart Fail, December 1, 2006; 8(8): 804 - 809. [Abstract] [Full Text] [PDF]
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Y. Li, G. Takemura, H. Okada, S. Miyata, R. Maruyama, L. Li, M. Higuchi, S. Minatoguchi, T. Fujiwara, and H. Fujiwara Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure Cardiovasc Res, September 1, 2006; 71(4): 684 - 694. [Abstract] [Full Text] [PDF]
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S. Genth-Zotz, S. von Haehling, A. P. Bolger, P. R. Kalra, R. Wensel, A. J.S. Coats, H.-D. Volk, and S. D. Anker The anti-CD14 antibody IC14 suppresses ex vivo endotoxin stimulated tumor necrosis factor-alpha in patients with chronic heart failure Eur J Heart Fail, June 1, 2006; 8(4): 366 - 372. [Abstract] [Full Text] [PDF]
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E. A. Jankowska, P. Ponikowski, M. F. Piepoli, W. Banasiak, S. D. Anker, and P. A. Poole-Wilson Autonomic imbalance and immune activation in chronic heart failure - Pathophysiological links Cardiovasc Res, June 1, 2006; 70(3): 434 - 445. [Abstract] [Full Text] [PDF]
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M. Odeh, E. Sabo, and A. Oliven Circulating levels of tumor necrosis factor-{alpha} correlate positively with severity of peripheral oedema in patients with right heart failure Eur J Heart Fail, March 1, 2006; 8(2): 141 - 146. [Abstract] [Full Text] [PDF]
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S. Rutschow, J. Li, H.-P. Schultheiss, and M. Pauschinger Myocardial proteases and matrix remodeling in inflammatory heart disease Cardiovasc Res, February 15, 2006; 69(3): 646 - 656. [Abstract] [Full Text] [PDF]
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S. Sola, M. Q.S. Mir, S. Lerakis, N. Tandon, and B. V. Khan Atorvastatin Improves Left Ventricular Systolic Function and Serum Markers of Inflammation in Nonischemic Heart Failure J. Am. Coll. Cardiol., January 17, 2006; 47(2): 332 - 337. [Abstract] [Full Text] [PDF]
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V. C. Mehra, V. S. Ramgolam, and J. R. Bender Cytokines and cardiovascular disease J. Leukoc. Biol., October 1, 2005; 78(4): 805 - 818. [Abstract] [Full Text] [PDF]
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H. Fukuta, D. C. Sane, S. Brucks, and W. C. Little Statin Therapy May Be Associated With Lower Mortality in Patients With Diastolic Heart Failure: A Preliminary Report Circulation, July 19, 2005; 112(3): 357 - 363. [Abstract] [Full Text] [PDF]
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S. S. Pedersen, P. A. Lemos, P. R. van Vooren, T. K.K. Liu, J. Daemen, R. A.M. Erdman, P. C. Smits, P. W.J.C. Serruys, and R. T. van Domburg Type D personality predicts death or myocardial infarction after bare metal stent or sirolimus-eluting stent implantation: A rapamycin-eluting stent evaluated at rotterdam cardiology hospital (RESEARCH) registry substudy J. Am. Coll. Cardiol., September 1, 2004; 44(5): 997 - 1001. [Abstract] [Full Text] [PDF]
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Y. Higuchi, C. F. McTiernan, C. B. Frye, B. S. McGowan, T. O. Chan, and A. M. Feldman Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-{alpha}-Induced Cardiomyopathy Circulation, April 20, 2004; 109(15): 1892 - 1897. [Abstract] [Full Text] [PDF]
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W. C. Levy and I. B. Hirsch Diabetes and heart failure: is insulin therapy the answer? J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1051 - 1053. [Full Text] [PDF]
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S. Aker, S. Belosjorow, I. Konietzka, A. Duschin, C. Martin, G. Heusch, and R. Schulz Serum but not myocardial TNF-{alpha} concentration is increased in pacing-induced heart failure in rabbits Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R463 - R469. [Abstract] [Full Text] [PDF]
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