(Chest. 2001;120:453-459.)
© 2001
American College of Chest Physicians
Effects of Vesnarinone on Peripheral Circulating Levels of Cytokines and Cytokine Receptors in Patients With Heart Failure*
A Report From the Vesnarinone Trial
Anita Deswal, MD;
Nancy J. Petersen, PhD;
Arthur M. Feldman, MD, PhD;
Bill G. White, PhD and
Douglas L. Mann, MD, FCCP
*
From the Winters Center for Heart Failure Research, Houston VA Medical Center, Cardiology Section (Drs. Deswal and Mann), Department of Medicine, and Veterans Affairs Health Services Research and Development Center of Excellence (Dr. Petersen), Baylor College of Medicine, Houston, TX; Cardiovascular Institute of the University of Pittsburgh (Dr. Feldman), Medical Health System, Pittsburgh, PA; and Clinical Cardiovascular Research (Dr. White), Gaithersburg, MD.
Correspondence to: Douglas L. Mann, MD, FCCP, Cardiology Research (151C), Houston Veterans Affairs Medical Center, 2002 Holcombe Blvd, Houston, TX 77030; e-mail: dmann{at}bcm.tmc.edu
 |
Abstract
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Study objectives: Proinflammatory cytokines may
contribute to disease progression in heart failure by virtue of the
direct toxic effects that these molecules exert on the heart and the
circulation. Accordingly, there is interest in developing therapeutic
agents with anticytokine properties that might be used as adjunctive
therapy to modulate proinflammatory cytokine levels in patients with
heart failure. Previous experimental studies suggested that vesnarinone
has potent anticytokine properties in vitro. Therefore,
we examined the effects of vesnarinone on circulating levels of
cytokines and cytokine receptors in a large-scale, multicenter,
clinical trial of patients with moderate-to-advanced heart failure: the
Vesnarinone Trial (VEST).
Methods: Circulating
levels of tumor necrosis factor (TNF)-
, soluble TNF-receptor type 1,
soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble
IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked
immunosorbent assay at baseline and at 24 weeks in patients who were
receiving placebo (n = 352), 30 mg of vesnarinone (n = 367),
and 60 mg of vesnarinone (n = 327).
Results:
Treatment with 30 mg and 60 mg of vesnarinone had no effect on
circulating levels of cytokines or cytokine receptors in patients with
advanced heart failure over a 24-week period.
Conclusions: In contrast to the potent anticytokine
effects observed with vesnarinone in experimental studies in
vitro, the results of this clinical study suggest that
vesnarinone does not have any measurable anticytokine effects in
vivo in patients with moderate-to-advanced heart
failure.
Key Words: cytokine • heart failure • interleukin-6 • receptor • soluble interleukin-6 receptor • soluble tumor necrosis factor-receptor type 1 • soluble tumor necrosis factor-receptor type 2 • tumor necrosis factor- • vesnarinone
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Introduction
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Previous
studies1
2
suggest that proinflammatory cytokines may
contribute to disease progression in heart failure by virtue of the
direct toxic effects that these molecules exert on the heart and the
circulation. Accordingly, there has been increasing interest in
developing therapeutic agents with anticytokine properties that might
be used as adjunctive therapy for patients with moderate-to-advanced
heart failure. Vesnarinone is a positive inotropic agent that enhances
cardiac contractility through multiple mechanisms,3
4
including an increase in the inward calcium current attributable to the
phosphodiesterase inhibitory properties of this
compound.4
5
Previous small-scale clinical
studies6
7
8
9
with vesnarinone have shown salutary effects
on the quality of life, as well as morbidity and mortality in patients
with advanced heart failure. However, the mechanisms for these
beneficial effects are unknown.
Relevant to the above discussion is the observation that vesnarinone
inhibits the production of proinflammatory cytokines in a variety of
human cell lines,10
11
12
as well as in
lipopolysaccharide-stimulated whole blood from patients with heart
failure.13
Based on these observations, it was postulated
that at least some of the beneficial effects of vesnarinone in heart
failure patients were secondary to the anticytokine effects of
vesnarinone.11
14
Accordingly, in order to more formally
test this possibility, we prospectively examined the effects of
vesnarinone in patients with moderate-to-advanced heart failure in a
large-scale, multicenter clinical trial: the Vesnarinone Trial
(VEST).15
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Materials and Methods
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Patient Population
The protocol specified that the first 1,200 patients enrolled in
the VEST were to be included in the analysis of cytokines and cytokine
receptors. The design, patient demographics, and results of the VEST
have been reported previously.15
Circulating Levels of Cytokines and Cytokine Receptors
Plasma tumor necrosis factor (TNF)-, interleukin (IL)-6,
soluble TNF-receptor type 1 (sTNFR1), soluble TNF-receptor type 2
(sTNFR2), and soluble IL-6 receptor (sIL-6R) levels were obtained at
baseline and at 24 weeks of follow-up for each patient. 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 receiving stable doses of angiotensin-converting enzyme
inhibitors, diuretics, digoxin, and/or vasodilators for 30 days prior
to obtaining baseline measurements. Circulating levels of cytokines and
cytokine receptors were measured using an enzyme-linked immunosorbent
assay (ELISA; R&D Systems; Minneapolis, MN) that measures "total"
TNF and IL-6 (ie, free [unbound] cytokine and cytokine
bound to receptors).16
17
18
There are several aspects of
the methodology used in the analysis of this large clinical database
that bear further emphasis. First, plasma samples at all 189 centers in
the VEST were collected using a standard protocol that was designed to
minimize ex vivo production and/or catabolism of cytokines.
That is, plasma samples were immediately stored on ice, the cells were
rapidly separated from the plasma (< 30 min), and endotoxin-free
ethylenediaminetetra-acetic acid tubes were used to collect
samples.19
20
To safeguard against the presence of
heterophile antibodies,21
which can lead to spuriously
high levels of cytokines in up to 15 to 20% of heart failure patients
(Douglas Mann, MD; unpublished observations; June 1996), all
cytokine assays were performed using at least one serial dilution to
ensure that the samples diluted appropriately; subsequent dilutions
were performed as necessary. All ELISAs were performed by two
experienced senior technicians who were familiar with the assays, and
who were blinded with respect to the treatment protocol of the patient.
All plasma samples were stored at - 70°C at the Core Cytokine
Laboratory at the Houston Veterans Affairs Medical Center in Houston,
TX. In preliminary control experiments, we determined that the process
of storing and shipping the plasma samples to the Core Laboratory
resulted in negligible change in the detectable levels of each cytokine
tested. After the completion of 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, WI.
Statistical Analysis
Neither the cytokine nor the cytokine-receptor data were
normally distributed; therefore, the data were subjected to logarithmic
transformation prior to all statistical analyses. However, in order to
permit comparison with results from other studies, both the cytokine
and cytokine-receptor data are presented as mean ± SEM on the
untransformed scale. Analysis of variance (ANOVA) was used to compare
continuous variables in the placebo, 30-mg vesnarinone, and 60-mg
vesnarinone groups at baseline. The 
2 test was
used for comparison of categoric variables. Cytokine levels at baseline
and at 24 weeks were compared between the treatment groups using a
repeated-measures factorial ANOVA. The fold change in cytokine and
cytokine-receptor levels (ie, ratio of levels at 24 weeks to
levels at baseline) as a function of survival was compared between the
treatment groups using a factorial ANOVA. Post hoc analysis
with the Tukey’s test was performed where appropriate. Data were
analyzed using software (SAS system for Windows, version 6.12; SAS
Institute, Cary, NC). A significant difference was said to exist
at p < 0.05.
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Results
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Patient Population
Of the 1,200 patients included in the analysis of cytokines and
cytokine receptors, 154 patients were excluded based on either
inadequate blood samples for the baseline and/or 24-week time points
(n = 136) or incorrect New York Heart Association (NYHA) class
(n = 18). There were 67 deaths within the first 24 weeks (18 deaths
in the placebo group, 19 deaths in the 30-mg vesnarinone group, and 30
deaths in the 60-mg vesnarinone groups). The patients who died within
the first 24 weeks were not included in the analysis. The final data
set consisted of a total of 1,046 patients with NYHA class III/IV heart
failure. Of the 1,046 patients included, 352 received placebo, 367
received 30 mg of vesnarinone, and 327 patients received 60 mg of
vesnarinone.
Table 1
shows the demographic characteristics of the study population. The mean
age of the patient cohort was 62 years, of which most (77%) were men.
Approximately 90% were in NYHA class III functional status at the time
of enrollment, and 60% of the patients were categorized as having an
ischemic cardiomyopathy. As shown, there were no significant
differences in age, sex, etiology of heart failure, ejection fraction,
serum sodium level, and weight among patients in the placebo, 30-mg
vesnarinone, and 60-mg vesnarinone groups. There was, however, a higher
proportion of NYHA class IV patients in the vesnarinone groups
(p = 0.02). These characteristics are similar to those previously
reported for the entire cohort of VEST patients.15
Circulating Levels of Cytokines and Cytokine Receptors
Table 2
shows the baseline values for the circulating cytokines and cytokine
receptors for patients who received placebo, 30 mg of vesnarinone, and
60 mg of vesnarinone. As shown, there were no significant differences
in baseline levels of cytokines or cytokine receptors among the three
treatment groups. Figure 1 shows the changes in TNF- and TNF receptors at 24 weeks compared to
baseline values. Figure 1
, top, A shows that
there was a small increase in the circulating levels of TNF- in each
of the three treatment groups at 24 weeks, which was statistically
significant in only the 30-mg vesnarinone group (p = 0.04). However,
there was no significant difference in the levels of TNF- as a
function of time among patients who received placebo, 30 mg of
vesnarinone, or 60 mg of vesnarinone (p = 0.77). Figure 1
,
middle, B, and bottom, C
shows that although there was a significant increase in the circulating
levels of sTNFR1 and sTNFR2 in each of the three treatment groups at 24
weeks (p < 0.001 for each group), there was no significant
difference in the levels of sTNFR1 or sTNFR2 as a function of time
between patients who received placebo, 30 mg of vesnarinone, or 60 mg
of vesnarinone (p = 0.99 and p = 0.77, respectively). Figure 2
shows the changes in IL-6 and sIL-6R at 24 weeks compared to baseline
values. As shown in Figure 2
, left, A, there was
a decrease in IL-6 levels in the placebo and 30-mg vesnarinone groups
at 24 weeks (statistically insignificant) and a trend toward a
significant increase in IL-6 at 24 weeks in the 60-mg vesnarinone group
(p = 0.07). However, there was no significant difference in the
levels of IL-6 as a function of time between patients who received
placebo, 30 mg of vesnarinone, or 60 mg of vesnarinone (p = 0.15).
Although there was an increase in sIL-6R levels in the placebo
(p = 0.03) group and no significant change in the 30-mg vesnarinone
(p = 0.88) or 60-mg vesnarinone (p = 0.14) groups at 24 weeks,
there was no significant difference (p = 0.21) in the levels of
sIL-6R as a function of time among patients who received placebo, 30 mg
of vesnarinone, or 60 mg of vesnarinone (Fig 2
, right,
B). Thus, when compared to placebo, neither treatment with
30 mg of vesnarinone nor 60 mg of vesnarinone led to a significant
decrease in circulating levels of cytokines or cytokine receptors at 24
weeks.
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Figure 2.. Circulating levels of IL-6 and sIL-6R in patients
with moderate-to-advanced heart failure. Circulating levels of IL-6
(left, A) and sIL-6R
(right, B) were measured on plasma
samples by ELISA at baseline and at 24 weeks in patients who were
receiving placebo, 30 mg of vesnarinone, and 60 mg of vesnarinone.
Patients receiving placebo are depicted by the closed circles, patients
receiving 30 mg of vesnarinone are depicted by the open circles, and
patients receiving 60 mg of vesnarinone are depicted by the open
squares.
|
|
Since pentoxifylline, another phosphodiesterase inhibitor, was
effective in reducing levels of TNF- in patients with idiopathic
dilated cardiomyopathy in a previous study,22
we also
examined vesnarinone-induced changes in cytokine levels in relation to
the etiology of heart failure. Figure 3
shows the fold change in TNF- and IL-6 levels from baseline to 24
weeks (ie, 24 weeks/baseline levels), in relation to the
etiology of heart failure in the three treatment groups. As shown in
the Figure 3
, the fold change in TNF- and IL-6 did not differ
significantly between patients with ischemic and nonischemic etiology
of heart failure in the three treatment groups.
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Figure 3.. Changes in cytokine levels in relation to etiology
of heart failure. The fold change in circulating levels of TNF-
(left, A) and IL-6 (right,
B) from baseline to 24 weeks are depicted for patients
who received placebo, 30 mg of vesnarinone, and 60 mg of vesnarinone.
Patients were classified based on ischemic (solid bars) and nonischemic
(open bars) etiology of heart failure. There were no significant
differences (p > 0.05) in the fold change in cytokine levels among
the three treatment groups by etiology of heart failure.
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Change in Cytokine Levels and Patient Mortality
Because vesnarinone had been shown to have a dose-dependent
adverse effect on mortality,15
we next examined
vesnarinone-induced changes in cytokines in relation to patient
mortality. During follow-up from the 24th week to a maximum of 78
weeks, there were 43 deaths (12.2%) in the placebo group, and 58
deaths (15.8%) and 48 deaths (14.7%) in the 30-mg vesnarinone group
and 60-mg vesnarinone group, respectively. In order to determine if the
changes in the cytokines levels were different in the patients who died
during the follow-up period, we compared the fold change in cytokine
and cytokine-receptor levels from baseline to 24 weeks in the three
treatment groups. Figure 4
shows the fold change in TNF- and IL-6 levels from baseline to 24
weeks in relation to mortality in the three treatment groups. As shown
in Figure 4
, left, A, the fold change in TNF-
levels was similar in the survivors and nonsurvivors in the three
different treatment groups. Figure 4
, right, B
shows that the fold change in IL-6 levels was not significantly
different in the survivors in the three different treatment groups. In
contrast, there was a significant (p < 0.01) dose-dependent increase
in IL-6 levels in the nonsurvivors who received vesnarinone. Post
hoc testing revealed a statistically significant increase in IL-6
levels in nonsurvivors in the 60-mg vesnarinone group when compared
with the nonsurvivors in the placebo group. There were no significant
differences in the fold change of soluble TNF- or IL-6 receptor
levels in relation to mortality among the three treatment groups (data
not shown).
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Figure 4.. Changes in cytokine levels in relation to patient
mortality. The fold change in circulating levels of TNF-
(left, A) and IL-6 (right,
B) from baseline to 24 weeks is depicted for patients
who received placebo, 30 mg of vesnarinone, and 60 mg of vesnarinone.
Patients were classified as survivors (solid bars) and nonsurvivors
(open bars).
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Discussion
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The results of this clinical study, in which we examined the
anticytokine properties of vesnarinone in patients with
moderate-to-advanced heart failure, suggest that neither the 30-mg/d
dosage nor 60 mg/d dosage of vesnarinone had any measurable effect on
the peripheral circulating levels of cytokines and cytokine receptors.
The finding that vesnarinone had no discernible effect on circulating
levels of TNF- and IL-6 in humans in vivo differs from
experimental data which showed that vesnarinone inhibited the
production of proinflammatory cytokines. Indeed, several in
vitro studies10
11
12
have shown that vesnarinone
suppresses the production of TNF- and IL-6 in various human cell
lines, including peripheral lymphocytes, monocytes, T-cell lines, and
microglial cells. Moreover, an in vivo study23
of endotoxemia in rabbits showed that IV vesnarinone reduced the
circulating levels of TNF-. Although the reasons for the discrepancy
between the previous in vitro/in vivo findings
are not clear, there are several possible explanations. First, the
doses of vesnarinone used in the VEST may have been less than those
used in experimental studies in vitro or in vivo.
Second, circulating levels of cytokines may not mirror changes in
cytokine levels in tissues. Thus, we cannot exclude the possibility
that vesnarinone decreased cytokine levels in the myocardium and/or
other tissue beds. Third, phosphodiesterase inhibitors such as
vesnarinone may not be able to suppress cytokine synthesis once
cytokine production has already been initiated in patients with heart
failure. Nevertheless, the recent experience22
with the
phosphodiesterase inhibitor pentoxifylline, which was shown to
significantly decrease TNF- levels in patients with idiopathic
dilated cardiomyopathy, would argue against this possibility. However,
we did not find any decrease in levels of TNF- in patients with an
ischemic or nonischemic etiology of heart failure in this study.
Fourth, the short-term effects of vesnarinone observed in experimental
studies may not be sustained following longer-term use of the drug;
that is, there may be an "escape phenomenon" following long-term
clinical use of vesnarinone. Finally, the metabolism of vesnarinone in
patients with heart failure may favor the generation of one or more
metabolites that lack anticytokine properties. It bears emphasis that
the results of the present study are entirely analogous to those that
were reported recently with amiodarone, which was shown to suppress
TNF- production in endotoxin-stimulated mononuclear
cells,24
but which had no measurable effect on peripheral
circulating levels of TNF- in a subset of patients with nonischemic
cardiomyopathy enrolled in the Survival Trial of Antiarrhythmic Therapy
in Congestive Heart Failure.25
A second interesting and potentially important finding in this study is
that there was a significant dose-dependent increase in IL-6 levels in
the vesnarinone-treated patients who died, when compared to the
nonsurvivors who received placebo (Fig 4 , right,
B). Although the mechanism for the increase in IL-6 levels
in the nonsurvivors who were treated with vesnarinone is not known, it
is interesting to note that previous reports have shown that the
treatment of patients with agents that elevate cyclic adenosine
monophosphate levels, such as dobutamine and pentoxifylline, has
resulted in increased circulating levels of IL-6.26
27
Accordingly, it is possible that an increase in the levels of cyclic
adenosine monophosphate mediated by the phosphodiesterase-inhibiting
effect of vesnarinone was responsible for the higher IL-6 levels seen
in patients treated with vesnarinone. The question of whether elevated
IL-6 levels may be used as a serologic marker for patients who are
likely to have an untoward outcome following the sustained use of
phosphodiesterase inhibitors will require further study.
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Conclusion
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As noted at the outset, there has been increased interest in
exploring the role of anticytokine strategies for patients with heart
failure. Historically, the use of vesnarinone in the VEST was one of
the first attempts to modulate proinflammatory cytokine levels in
patients with heart failure. Although the present study suggests that
the doses of vesnarinone used in VEST did not have anticytokine effects
in patients with heart failure, the concept that anticytokine therapy
may be useful in patients with heart failure is suggested by two
studies.22
28
As one example, treatment of patients
with dilated cardiomyopathy with pentoxifylline for 6 months was
associated with an improvement in left ventricular ejection performance
and clinical outcomes, as well as a decrease in circulating levels of
TNF- when compared to a comparable group of age-matched placebo
control subjects.22
Moreover, we have previously
shown28
that use of a soluble TNF- antagonist can lead
to an improvement in clinical outcomes and a decrease in the
circulating levels of biologically active TNF- in patients with
moderate heart failure. While the results of these two clinical studies
must be regarded as provisional because of the relatively small numbers
of patients and the relatively short duration of follow-up, these
studies do suggest that it is both safe and potentially feasible to
modulate proinflammatory cytokine levels in patients with heart
failure.
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Acknowledgements
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The authors acknowledge the secretarial assistance
of Jana Grana, as well as the technical assistance of Adrienne Chee,
Dorellyn Lee-Jackson, and Wendy Skinner. We also thank Dr. Andrew
Schafer for his guidance and support.
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Footnotes
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Abbreviations: ANOVA = analysis of variance;
ELISA = enzyme-linked immunosorbent assay; IL = interleukin;
NYHA = New York Heart Association; sIL-6R = soluble interleukin-6
receptor; sTNFR1 = soluble tumor necrosis factor-receptor type 1;
sTNFR2 = soluble tumor necrosis factor-receptor type 2; TNF = tumor
necrosis factor; VEST = Vesnarinone Trial
The study was performed at the Houston Veterans Affairs Medical Center
and was supported by funds from Otsuka America Pharmaceuticals.
Dr. Deswal is a recipient of a Clinical Research Career Development
Award (CRCD No. 712B) from the Veterans Affairs Cooperative Studies
Program.
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References
|
|---|
-
Packer, M (1995) Is tumor necrosis factor an important neurohormonal mechanism in chronic heart failure? Circulation 92,1379-1382[Free Full Text]
-
Seta, Y, Shan, K, Bozkurt, B, et al (1996) Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail 2,243-249[CrossRef][Medline]
-
Iijima, T, Taira, N (1987) Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther 240,657-662[Abstract/Free Full Text]
-
Rapundalo, ST, Lathrop, DA, Harrison, SA, et al (1988) Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212. Naunyn Schmiedebergs Arch Pharmacol 338,692-698[CrossRef][ISI][Medline]
-
Endoh, M, Yanagisawa, T, Taira, N, et al (1986) Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation 73,111-117
-
Feldman, AM, Becker, LC, Llewellyn, MP, et al (1988) Evaluation of a new inotropic agent, OPC-8212, in patients with dilated cardiomyopathy and heart failure. Am Heart J 116,771-777[CrossRef][ISI][Medline]
-
Asanoi, H, Sasayama, S, Kameyama, T, et al (1989) Sustained inotropic effects of a new cardiotonic agent. OPC-8212 in patients with chronic heart failure. Clin Cardiol 12,133-138[ISI][Medline]
-
. OPC-8212 Multicenter Research Group (1990) A placebo-controlled, randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure. Cardiovasc Drugs Ther 4,419-426[CrossRef][ISI][Medline]
-
Feldman, AM, Bristow, MR, Parmley, WW, et al (1993) Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med 329,149-155[Abstract/Free Full Text]
-
Shioi, T, Matsumori, A, Matsui, S, et al (1993) Inhibition of cytokine production by a new inotropic agent, vesnarinone, in human lymphocytes, t cell line, and monocytic cell line. Life Sci 54,PL11-PL16
-
Matsumori, A, Ono, K, Sato, Y, et al (1996) Differential modulation of cytokine production by drugs: implications for therapy in heart failure. J Mol Cell Cardiol 28,2491-2499[CrossRef][ISI][Medline]
-
Jiang, H, Bielekova, B, Okazaki, H, et al (1999) The effect of vesnarinone on TNF production in human peripheral blood mononuclear cells and microglia: a preclinical study for the treatment of multiple sclerosis. J Neuroimmunol 97,134-145[CrossRef][ISI][Medline]
-
Matsumori, A, Shioi, T, Yamada, T, et al (1994) Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure. Circulation 89,955-958[Abstract/Free Full Text]
-
Packer, M (1993) The search for the ideal positive inotropic agent. N Engl J Med 329,201-202[Free Full Text]
-
Cohn, JN, Goldstein, SO, Greenberg, BH, et al (1998) A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure: Vesnarinone Trial Investigators. N Engl J Med 339,1810-1816[Abstract/Free Full Text]
-
R&D Systems Cytokine Bulletin, Spring. Minneapolis, MN: R&D Systems, 1994
-
Torre-Amione, G, Kapadia, S, Benedict, CR, et al (1996) Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 27,1201-1206[Abstract]
-
Torre-Amione, G, Kapadia, S, Lee, J, et al (1996) Tumor necrosis factor- and tumor necrosis factor receptors in the failing human heart. Circulation 93,704-711[Abstract/Free Full Text]
-
Riches, P, Gooding, R, Millar, BC, et al (1992) Influence of collection and separation of blood samples on plasma IL-1, IL-6 and TNF- concentrations. J Immunol Methods 153,125-131[CrossRef][ISI][Medline]
-
Thavasu, PW, Longhurst, S, Joel, SP, et al (1992) Measuring cytokine levels in blood: importance of anticoagulants, processing, and storage conditions. J Immunol Methods 153,115-124[CrossRef][ISI][Medline]
-
Boscato, LM, Stuart, MC (1986) Incidence and specificity of interference in two-site immunoassays. Clin Chem 32,1491-1495[Abstract/Free Full Text]
-
Sliwa, K, Skudicky, D, Candy, G, et al (1998) Randomized investigation of effects of pentoxifylline on left ventricular performance in idiopathic dilated cardiomyopathy. Lancet 351,1091-1093[CrossRef][ISI][Medline]
-
Takeuchi, K, del Nido, PJ, Ibrahim, AE, et al (1999) Vesnarinone and amrinone reduce the systemic inflammatory response syndrome. Thorac Cardiovasc Surg 117,375-382
-
Matsumori, A, Ono, K, Nishio, R, et al (1997) Amiodarone inhibits production of tumor necrosis factor- by human mononuclear cells: a possible mechanism for its effect in heart failure. Circulation 96,1386-1389[Abstract/Free Full Text]
-
Oral, H, Fisher, SG, Fay, WP, et al (1999) Effects of amiodarone on tumor necrosis factor- levels in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 83,388-391[CrossRef][ISI][Medline]
-
Deng, MC, Erren, M, Lutgen, A, et al (1996) Interleukin-6 correlates with hemodynamic impairment during dobutamine administration in chronic heart failure. Int J Cardiol 57,129-134[CrossRef][ISI][Medline]
-
Staudinger, T, Presterl, E, Graninger, W, et al (1996) Influence of pentoxifylline on cytokine levels and inflammatory parameters in septic shock. Intensive Care Med 22,888-893[ISI][Medline]
-
Deswal, A, Bozkurt, B, Seta, Y, et al (1999) A phase I trial of tumor necrosis factor receptor (p75) fusion protein (TNFR: Fc) in patients with advanced heart failure. Circulation 99,3224-3226[Abstract/Free Full Text]
TOP
Abstract
Introduction
