Review
This Review is part of a thematic series on Chemokines and Cytokines, which includes the following articles:
Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future
Infarction/Remodeling
Cytokines in Microinfarction
Chemokines/Cytokines
Peter Liu, Guest Editor
Inflammatory Mediators and the Failing Heart
Past, Present, and the Foreseeable Future
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Douglas L. Mann
Abstract—Recent studies have identified the importance of proinflammatory mediators in the development and progression
of heart failure. The growing appreciation of the pathophysiological consequences of sustained expression of
proinflammatory mediators in preclinical and clinical heart failure models culminated in a series of multicenter clinical
trials that used “targeted” approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart
failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of
important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This
review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we
have learned from the negative clinical trials, as well as the potential direction of future research in this area. (Circ Res.
2002;91:988-998.)
Key Words: tumor necrosis factor 䡲 inflammatory mediators 䡲 clinical trial 䡲 etanercept 䡲 infliximab
“If at first you do not succeed, you are running about
average.” —M.H. Alderson
patients with moderate to advanced heart failure. However, as
recently reported, these targeted approaches have resulted in
worsening heart failure.3,4 These discouraging results have
raised a number of important questions about what role, if
any, proinflammatory cytokines play in the pathogenesis of
heart failure. To this end, in the present review, we will
summarize the tremendous growth of knowledge that has
taken place in this field, with a focus on what we have learned
from the negative clinical trials, as well as the potential
direction of future research in this area.
A
lthough clinicians have recognized the pathophysiological importance of myocardial inflammation as
early as 1669,1 the formal recognition that inflammatory
mediators were activated in the setting of heart failure did
not occur for another three centuries. Since the sentinel
description of inflammatory cytokines in patients with
heart failure in 1990,2 there has been a growing interest in
the role that these molecules play in regulating cardiac
structure and function, particularly regarding their potential
role in disease progression in heart failure. The growing
appreciation of the pathophysiological consequences of
sustained expression of proinflammatory mediators in preclinical and clinical heart failure models culminated in a
series of multicenter clinical trials that used “targeted”
approaches to neutralize tumor necrosis factor (TNF) in
Scientific Rationale for Studying
Inflammatory Mediators in Heart Failure
The portfolio of cytokines that will constitute the focus of
much of the present review includes TNF and the interleukin
(IL)-1 family (including the recently described member
IL-185) and the IL-6 family of cytokines. These molecules
Original received August 21, 2002; revision received October 4, 2002; accepted October 11, 2002.
From the Winters Center for Heart Failure Research, the Cardiology Section, Department of Medicine, Veterans Administration Medical Center,
Methodist Hospital, and Baylor College of Medicine, Houston, Tex.
Correspondence to Douglas L. Mann, MD, Winters Center for Heart Failure Research, MS 524, 6565 Fannin, Houston, TX 77030. E-mail
[email protected]
© 2002 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org
DOI: 10.1161/01.RES.0000043825.01705.1B
988
Mann
Deleterious Effects of Inflammatory Mediators in Heart Failure
Left ventricular dysfunction
Pulmonary edema in humans
Cardiomyopathy in humans
Reduced skeletal muscle blood flow
Endothelial dysfunction
Anorexia and cachexia
Receptor uncoupling from adenylate cyclase experimentally
Activation of the fetal gene program experimentally
Cardiac myocyte apoptosis experimentally
Modified from Kapadia S, Dibbs Z, Kurrelmeyer K, Kalra D, Seta Y, Wang F,
Bozkurt B, Oral H, Sivasubramanian N, Mann DL. The role of cytokines in the
failing human heart. In: Crawford M, ed. Cardiology Clinics. Philadelphia, Pa:
WB Saunders; 1998:645– 656,82 by permission.
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have been referred to as proinflammatory cytokines, insofar
as they were traditionally thought to be derived exclusively
from the immune system and were therefore considered to be
primarily responsible for mediating inflammatory responses
in tissues. However, these inflammatory mediators are now
known to be expressed by all nucleated cell types residing in
the myocardium, including the cardiac myocyte, thus suggesting that these molecules may do more than simply
orchestrate inflammatory responses in the heart.6 The interest
in understanding the role of inflammatory mediators in heart
failure arises from the observation that many aspects of the
syndrome of heart failure can be explained by the known
biological effects of proinflammatory cytokines (Table). That
is, when expressed at sufficiently high concentrations, such as
those that are observed in heart failure, cytokines are sufficient to mimic some aspects of the so-called heart failure
phenotype, including (but not limited to) progressive left
ventricular (LV) dysfunction, pulmonary edema, LV remodeling, fetal gene expression, and cardiomyopathy.7–9 Thus,
the “cytokine hypothesis”10 for heart failure holds that heart
failure progresses, at least in part, as a result of the toxic
effects exerted by endogenous cytokine cascades on the heart
and the peripheral circulation. It bears emphasis that the
cytokine hypothesis does not imply that cytokines cause heart
failure, per se, but rather that the overexpression of cytokine
cascades contributes to the disease progression of heart
failure. Thus, the elaboration of cytokines, much like the
elaboration of neurohormones, may represent a biological
mechanism that is responsible for worsening heart failure.
As discussed above, there is now a substantial body of
evidence suggesting that the sustained expression of cytokines
produces frank maladaptive effects in the heart. Although the
deleterious effects of cytokines on myocardial function have
received the most attention thus far, it bears emphasis that
cytokines may also produce deleterious effects on LV structure
(remodeling) and endothelial function. Accordingly, in the
following section, we will discuss the studies that form the
scientific basis for studying the role of proinflammatory mediators in the failing heart.
Effects of Cytokines on LV Function
The observation that proinflammatory cytokines are capable of
modulating LV function was first reported in a series of
Inflammatory Mediators and Heart Failure
989
important experimental studies showing that direct injections of
TNF would produce hypotension, metabolic acidosis, hemoconcentration, and death within minutes, thus mimicking the cardiac/hemodynamic response seen during endotoxin-induced septic
shock.11 Furthermore, injections of antibodies raised against
TNF were subsequently shown to attenuate the hemodynamic
collapse seen in endotoxin shock. Studies in dogs have shown
that a single infusion of TNF results in abnormalities of systolic
function within the first 24 hours of infusion.12,13 Experimental
studies in rats have shown that circulating concentrations of TNF
that overlap those observed in patients with heart failure are
sufficient to produce persistent negative inotropic effects that are
detectable at the level of the cardiac myocyte; moreover, the
negative inotropic effects of TNF are completely reversible
when the TNF infusion is stopped.7 Subsequent studies in
transgenic mice with targeted overexpression of TNF in the
cardiac compartment have shown that forced overexpression of
TNF results in depressed LV ejection performance and that the
depressed LV ejection performance was dependent on TNF
“gene dosage.”9,14
Regarding the potential mechanisms for the deleterious effects of TNF on LV function, the literature suggests that TNF
modulates myocardial function through at least two different
pathways: (1) an immediate pathway that is manifest within
minutes and is mediated by activation of the neutral sphingomyelinase pathway15 and (2) a delayed pathway that requires
hours to days to develop and is mediated by NO-mediated
blunting of ␤-adrenergic signaling.16,17 Insofar as the basic
cellular and molecular mechanisms that are responsible for the
immediate and delayed negative inotropic effects of TNF have
been reviewed recently in considerable detail, they will not be
discussed further in the present review.18,19 Although both IL-1
and IL-6 have been shown to produce negative inotropic effects
in various experimental models,20 –22 the signal transduction
pathways that are responsible for the negative inotropic effects
of IL-6 have not been clearly established. In contrast, the
negative inotropic effects of IL-1 appear to be mediated, at least
in part, through the production of NO (ie, the delayed pathway).23,24 Recently, it has been suggested that TNF and IL-1
may produce negative inotropic effects indirectly through activation and/or release of IL-18, which is a recently described
member of the IL-1 family of cytokines.25 Relevant to the
present discussion is the observation that specific blockade of
IL-18 using neutralizing IL-18 binding protein leads to an
improvement in myocardial contractility in atrial tissue that has
been subjected ischemia/reperfusion injury.5 Although the signaling pathways that are responsible for the IL-18 –induced
negative inotropic effects have not been delineated thus far, it is
likely that they will overlap those for IL-1, given that the IL-18
receptor complex uses components of the IL-1 signaling chain.25
Effects of Proinflammatory Cytokines
on LV Remodeling
The term LV remodeling has been used to describe the
multitude of changes that occur in cardiac shape, size, and
composition in response to myocardial injury. Inflammatory
mediators have a number of important effects that may play
an important role in the process of LV remodeling, including
myocyte hypertrophy,26 alterations in fetal gene expression,9
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Figure 1. LV remodeling in a transgenic (TG) mouse model of
TNF overexpression. Magnetic resonance images of the heart
were obtained from 24-week-old TG mice with targeted TNF
overexpression (A, B, and C) and an age-matched control (WT)
mouse (D, E, and F). As shown, there was significant LV dilation
in the animal harboring the TNF transgene in the cardiac compartment. Reproduced from Kubota T, McTiernan CF, Frye CS,
Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman
AM. Dilated cardiomyopathy in transgenic mice with cardiac
specific overexpression of tumor necrosis factor-␣. Circ Res.
1997;81:627– 635, by permission of the American Heart Association ©1997.
and progressive myocyte loss through apoptosis.27 In addition
to the above effects, there are several lines of evidence
suggesting that TNF may promote LV remodeling through
alterations in the extracellular matrix. First, when concentrations of TNF that overlap those observed in patients with
heart failure are infused continuously in rats, there is a
time-dependent change in LV dimension that is accompanied
by progressive degradation of the extracellular matrix. Moreover, similar findings have been reported after a single
infusion of TNF in dogs.13 Second, recent studies in transgenic mice with targeted overexpression of TNF have shown
that these mice develop progressive LV dilation. For example, Kubota et al9 showed that a transgenic mouse line that
overexpressed TNF in the cardiac compartment developed
progressive LV dilation over a 24-week period of observation
(Figure 1).9 Similar findings have also been reported by
Bryant et al28 and Sivasubramanian et al,29 who observed
identical findings with respect to LV dysfunction and LV
dilation in transgenic mice with targeted overexpression of
TNF in the heart. With respect to the mechanisms that are
involved in TNF-induced LV dilation, it has been suggested
that TNF-induced activation of matrix metalloproteinases
(MMPs) is responsible for this effect.29,30 As shown in
Figures 2 and 3, respectively, there was progressive loss of
fibrillar collagen and increased MMP activation in the hearts
of the transgenic mice overexpressing TNF in the cardiac
compartment. The dissolution of the fibrillar collagen weave
that surrounds the individual cardiac myocytes and links the
myocytes together would be expected to allow for rearrangement (slippage) of myofibrillar bundles within the ventricular
wall.31 However, Figure 2 shows that long-term stimulation
(ie, 8 to 12 weeks) with TNF resulted in an increase in
fibrillar collagen content that was accompanied by decreased
MMP activity (Figure 3) and increased expression of the
tissue inhibitors of MMPs (TIMPs [Figure 3]). Taken to-
Figure 2. Effects of sustained proinflammatory cytokine expression on myocardial ultrastructure and collagen content. Panels A
through C show representative transmission electron micrographs in littermate controls (A) and the TNF transgenic mice at
4 (B) and 8 (C) weeks of age. The transmission electron micrographs from the littermate control mice at 4 weeks (A) revealed
a characteristic linear array of sarcomere and myofibril. In contrast, the myofibrils in the 4-week-old TNF transgenic mice were
less organized, with loss of sarcomeric registration observed in
many of the sections (B). The ultrastructural abnormalities in the
TNF transgenic mice were further exaggerated in the 12-weekold TNF transgenic mice, which showed a significant loss of
sarcomere registration and myofibril disarray (C). Panels D
through F show representative scanning electron micrographs in
littermate controls (D) and TNF transgenic mice at 4 (E) and 8 (F)
weeks of age. Panel E shows that there was a significant loss of
fibrillar collagen in the TNF transgenic mice at 4 weeks of age
compared with age-matched littermate controls (D). However,
as the TNF transgenic mice aged (ie, at 12 weeks), there was an
obvious increase in myocardial fibrillar collagen content. Panel
G illustrates the myocardial collagen content as determined by
picrosirius red staining. There was a loss of myocardial collagen
content at 4 weeks of age in the TNF transgenic (MHCsTNF)
mice that was later followed by a progressive increase in myocardial collagen content at 8 and 12 weeks of age. *Significantly
different from littermate value. Reproduced from Sivasubramanian N, Coker ML, Kurrelmeyer KM, MacLellan WR, DeMayo FJ,
Spinale FG, Mann DL. Left ventricular remodeling in transgenic
mice with cardiac restricted overexpression of tumor necrosis
factor. Circulation. 2001;104:826 – 831, by permission of the
American Heart Association ©2001.
gether, these observations suggest that sustained myocardial
inflammation provokes time-dependent changes in the balance between MMP activity and TIMP activity. That is,
during the early stages of inflammation, there is an increase in
the ratio of MMP activity to TIMP levels that fosters LV
dilation. However, with chronic inflammatory signaling,
there is a time-dependent increase in TIMP levels, with a
resultant decrease in the ratio of MMP activity to TIMP
activity and a subsequent increase in myocardial fibrillar
collagen content. Although the molecular mechanisms that
are responsible for the transition between excessive degradation and excessive synthesis of the extracellular matrix are
not know, studies have been performed in experimental
models of chronic injury/inflammation in an array of different
organs, including liver, lung, and kidney, wherein an initial
increase in MMP expression is superseded by increased
TIMP expression and increased expression of a number of
fibrogenic cytokines, most notably transforming growth
factor-␤.32,33 Thus, excessive activation of proinflammatory
cytokines may contribute to LV remodeling through a variety
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Figure 3. Effects of sustained proinflammatory cytokine expression on MMP
activity and TIMP levels. Panel A shows
a zymogram of total MMP activity in the
TNF transgenic (MHCsTNF) mice and
littermate (LM) control mice at 4, 8, and
12 weeks of age. Panel B summarizes
the results of group data for total MMP
zymographic activity. MMP activity was
significantly (*P⬍0.001) greater in the
MHCsTNF mice at 4 weeks of age; MMP
activity was no different from that in LM
control mice at 8 and 12 weeks of age.
Panel C depicts the time-dependent
changes in TIMP levels at 4, 8, and 12
weeks in the MHCsTNF and LM control
mice. At 4 weeks of age, TIMP-1 levels
were significantly (*P⬍0.001) less in the
MHCsTNF mice at 4 weeks of age; however, TIMP-1 levels increased progressively in the MHCsTNF mice from 8 to
12 weeks of age. Panel D depicts the
time-dependent changes in the ratio of
MMP activity to TIMP levels in the MHCsTNF and LM control mice. As shown, at 4 weeks of age, the ratio of MMP activity to TIMP-1 levels was significantly greater in the
MHCsTNF mice, thus favoring collagen degradation; however, the ratio of MMP activity to TIMP-1 decreased progressively from 8 to
12 weeks of age, thus favoring collagen accumulation. Reproduced from Sivasubramanian N, Coker ML, Kurrelmeyer K, DeMayo F,
Spinale FG, Mann DL. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor.
Circulation. 2001;826 – 831, by permission of the American Heart Association ©2001.
of different mechanisms that involve both the myocyte and
nonmyocyte components of the myocardium.
Effects of Proinflammatory Mediators on
Endothelial Function
In addition to the effects of inflammatory mediators on
cardiac structure and function, there is growing evidence that
the concentrations of inflammatory mediators that exist in
heart failure are sufficient to contribute to endothelial dysfunction. The functional role of TNF in modulating endothelial function has been suggested in studies by Agnoletti et
al,34 who have demonstrated that the serum of patients with
heart failure induces apoptosis and downregulates endothelial
constitutive NO synthase in human umbilical vein endothelial
cells. The importance of TNF in their studies was suggested
by experiments in which an anti-TNF antibody partially
antagonized the effects of heart failure sera on endothelial
cell apoptosis.34 The role of TNF-induced endothelial dysfunction is further supported by studies by Anker et al,35 who
have shown that circulating TNF levels are correlated inversely with peak blood flow in heart failure patients,
independently of age, ejection fraction, peak oxygen consumption, and New York Heart Association (NYHA) class,
thus suggesting that TNF might be contribute to peripheral
skeletal muscle weakness/fatigue in patients with heart failure. Finally, in a recent clinical study that used a soluble TNF
antagonist (etanercept) to neutralize TNF, there was a shortterm improvement in forearm mediated blood flow that was
fully reversible after the cessation of therapy.36
Clinical Rationale for Studying Inflammatory
Mediators in Heart Failure
As noted at the outset, the interest in understanding the role of
inflammatory mediators in heart failure arises from the
observation that many aspects of the syndrome of heart
failure can be explained by the known biological effects of
proinflammatory cytokines (Table). A second rationale for
studying inflammatory mediators in heart failure is that the
pattern of expression of cytokines is very similar to that
observed with the classic neurohormones (eg, angiotensin II
and norepinephrine) that are believed to play an important
role in disease progression in heart failure (see review37).
That is, proinflammatory cytokines, including TNF, IL-1␤,
and IL-6, are expressed in direct relation to worsening NYHA
functional classification. Moreover, the observation that a
variety of redundant inflammatory mediators are activated in
heart failure also has potential therapeutic implications for the
types of antiinflammatory strategies that should be used in
clinical trials. Insofar as proinflammatory cytokines were
initially identified in patients with cardiac cachexia,2 there is
a common misperception that these molecules are elaborated
only in patients with end-stage heart failure. However, as
reported in a number of studies38 – 40 and as shown in Figure
4, proinflammatory molecules are activated earlier in heart
failure (ie, NYHA class II) than are the classic neurohormones, which tend to be activated in the latter stages of heart
failure (ie, NYHA classes III and IV).41 Another clinical
similarity between both inflammatory mediators and classic
neurohormones is that circulating levels of both families of
molecules have prognostic importance in the setting of heart
failure.42 As shown in Figure 5A, data from the multicenter
Vesnarinone Trial (VEST) have shown that there is a significant overall difference in survival as a function of increasing
TNF levels, with the worst survival in patients with TNF
levels ⬎75th percentile.40 Similar findings have been observed with respect to the Kaplan-Meier analysis of circulating levels of IL-6 (Figure 5B). This analysis further showed
that levels of soluble TNF receptor type 1 (sTNFR1) and
soluble TNF receptor type 2 (sTNFR2) are highly predictive
of adverse outcomes, consistent with prior reports (Figures
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Figure 4. TNF levels in patients with class I to IV heart failure.
Compared with age-matched control subjects (open bar), there
was a progressive increase in serum TNF-␣ levels in direct relation to decreasing functional heart failure classification. The
solid bars denote values for patients enrolled in Studies of Left
Ventricular Dysfunction (SOLVD)38; the shaded bar denotes values for NYHA class IV patients who were undergoing cardiac
transplantation.65 *Significantly different from normal. Reproduced from Seta Y, Shan K, Bozkurt B, Oral H, Mann DL. Basic
mechanisms in heart failure: the cytokine hypothesis. J Card
Fail. 1996;2:243–249, by permission of Churchill Livingstone
©1996.
5C and 5D).34,43 Indeed, a univariate Cox analysis of the
VEST cytokine database has shown that TNF (P⫽0.01), IL-6
(P⫽0.0003), sTNFR1 (P⫽0.0001), and sTNFR2 (P⫽0.0001)
are significant univariate predictors of mortality. Moreover,
when the cytokine and/or cytokine receptor was separately
entered into a multivariate Cox proportional hazards model
that included age, sex, etiology of heart failure, NYHA class,
ejection fraction, and serum sodium, TNF, IL-6, sTNFR1,
and sTNFR2 remained significant independent predictors of
mortality, along with NYHA class and ejection fraction.40
A third rationale for studying the role of proinflammatory
mediators in the setting of heart failure stems from the growing
evidence that there are critical interactions between inflammatory mediators and the mediators of the classic neurohormonal
Figure 5. Kaplan-Meier survival analysis. The circulating levels
of TNF (A), IL-6 (B), sTNFR1 (C), and sTNFR2 (D) were examined
in relation to patient survival during follow-up (mean duration 55
weeks; maximum duration 78 weeks). For this analysis, the circulating levels of cytokines and cytokine receptors were arbitrarily divided into quartiles. Reproduced with permission from
Deswal A, Petersen NJ, Feldman AM, Young JB, White BG,
Mann DL. Cytokines and cytokine receptors in advanced heart
failure: an analysis of the cytokine database from the Vesnarinone Trial (VEST). Circulation. 2001;103:2055–2059, by permission of the American Heart Association ©2001.
systems. Indeed, over the past two decades, our perception of the
role of angiotensin II in the cardiovascular system has changed
dramatically. Whereas angiotensin II has been traditionally
viewed as a circulating neurohormone that stimulated the constriction of vascular smooth muscle cells, aldosterone release
from the adrenal gland, sodium reabsorption in the renal tubule,
and/or as a stimulus for growth of cardiac myocytes or fibroblasts,44 it is becoming increasing apparent that angiotensin II
provokes inflammatory responses in a variety of different tissues
and cell and tissue types. Mechanistically, angiotensin II activates a redox-sensitive transcription factor, termed nuclear
factor-␬B,45 that is critical for initiating the coordinated expression of classic components of the myocardial inflammatory
response, including increased expression of proinflammatory
cytokines, NO, chemokines, and cell adhesion molecules.46
Moreover, recent experimental studies have shown that pathophysiologically relevant concentrations of angiotensin II are
sufficient to provoke TNF mRNA and protein synthesis in the
adult heart through a nuclear factor-␬B– dependent pathway47
and that ACE inhibitors decrease the short-term expression of
inflammatory mediators in the heart in a chronic infarct model.48
Finally, clinical studies that have examined long-term administration of ACE inhibitors or angiotensin receptor blockers have
shown that whereas ACE inhibitors have mixed results in terms
of inhibiting proinflammatory cytokines,49,50 angiotensin type 1
receptor antagonists have consistently led to significant decreases in circulating levels of inflammatory mediators (TNF)
and/or cell adhesion molecules (intercellular adhesion
molecule-1 and vascular adhesion molecule-1) in patients with
heart failure.50,51 Similarly, findings have recently been reported
for the use of ␤-adrenergic– blocking agents in experimental and
clinical heart failure studies. That is, ␤-adrenergic blockade with
a ␤1-selective adrenergic antagonist has been shown to prevent
the expression of proinflammatory mediators in an experimental
model of postinfarct LV remodeling.52 In a subset analysis of the
Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF),53 treatment with metoprolol did
not lead to a decrease in the level of proinflammatory mediators,54 whereas in a different study, the use of a nonselective
␤1,2-adrenergic antagonist with ancillary antioxidant properties
(carvedilol) resulted in a significant reduction in the transcardiac
production of TNF in a small number of patients.55 It remains
unclear whether the differences in these two studies are related to
the differences in selective versus nonselective ␤-adrenergic
blockade, differences in ancillary properties between metoprolol
and carvedilol, differences in the degree of ACE inhibition in the
two studies, or a sample bias. Nonetheless, the aggregate data
suggest that there are important interactions between the reninangiotensin/adrenergic systems and proinflammatory cytokines;
moreover, there is increasing evidence that many of the conventional therapies for heart failure may work, at least in part,
through the modulation of proinflammatory cytokines.
Inflammatory Mediators as Therapeutic
Targets in Heart Failure
The rationale for using antiinflammatory strategies in patients
with heart failure is 3-fold: first, as noted above, the excessive
elaboration of proinflammatory cytokines appears to mimic
many aspects of the heart failure phenotype; second, many of
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Figure 6. Therapeutic strategies for
antagonizing proinflammatory mediators. TNF gene transcription is mediated, in part, by activation of NF-␬B.
Agents that increase intracellular levels
of cAMP (➀), such as vesnarinone,
pentoxifylline, milrinone, thalidomide,
and thalidomide analogues (CelSids),
decrease the level of inflammatory
mediators through transcriptional
blockade of inflammatory gene expression. Agents such as dexamethasone
and prednisone and some p38 inhibitors suppress inflammation by blocking
the translation of inflammatory mediators (➁). Secreted TNF can be neutralized (➂) by soluble TNF antagonists
(etanercept) or by neutralizing antibodies (infliximab) that prevent TNF from
binding to its cognate type 1 (p55) and
type 2 (p75) TNF receptors. In addition
to these targeted approaches, immunomodulatory strategies with IVIG (➃) and
immune modulation therapy with irradiated whole blood have been used.
the deleterious effects of inflammatory mediators are potentially reversible once inflammation subsides; and third, heart
failure remains a progressive disease process despite optimal
therapy with ACE inhibitors and ␤-blockers. As shown in
Figure 6, the biological effects of proinflammatory mediators
can be antagonized through transcriptional or translational
approaches or by so-called biological response modifiers,
which bind and/or neutralize soluble mediators (eg, TNF or
IL-1␤). In addition, there are several novel “immunomodulatory strategies” that alter the levels of inflammatory mediators through multiple mechanisms. The clinical studies that
have attempted to suppress proinflammatory cytokine production in patients with heart failure using transcriptional
and/or translational approaches have been discussed in detail
in several recent reviews56 –58 and will be discussed only
briefly in the present review. Accordingly, the remaining part
of the present review will focus on the recent series of clinical
trials that have used targeted approaches that antagonize TNF
as well as the studies that have used immunomodulatory
therapies that decrease the levels of inflammatory mediators.
Transcriptional and/or Translational Approaches
Both pentoxifylline and thalidomide have been used successfully in small studies involving patients with moderate to
advanced heart failure. As shown in Figure 6, both of these
agents are believed to affect the synthesis of inflammatory
mediators by blocking their transcriptional activation. Sliwa
et al59 studied the effects of pentoxifylline in patients with
dilated cardiomyopathy and NYHA class II and III heart
failure.
A total of 14 patients received pentoxifylline three times daily
at a dose of 400 mg, and an equal number received placebo. The
primary end points of the 6-month study were NYHA functional
class and LV function. Four patients died as a result of
progressive pump dysfunction during the 6-month study period,
all in the placebo group. At the end of 6 months, there was an
improvement in functional class in the pentoxifylline group,
whereas there was functional deterioration in the placebo group.
In addition, there was a significant increase in the ejection
fraction in the pentoxifylline group, whereas there was no
significant change in the placebo group. An important observation was that TNF levels fell significantly in the pentoxifylline
group, whereas there was no significant change in the TNF
levels in the placebo group. Preliminary reports from an openlabel study in a small number of patients have also shown that
treatment with thalidomide leads to a significant improvement in
6-minute walking distance and a trend toward a significant
improvement in the quality of life and LV ejection performance.60 The effects of thalidomide are currently being tested in
a larger ongoing clinical trial in Europe.
Targeted Anticytokine Approaches Using
Biological Response Modifiers
Two different targeted approaches have been taken to selectively antagonize proinflammatory cytokines in heart failure
patients. In the first approach, investigators have used recombinant human TNF receptors that act as “decoys” to bind
TNF, thereby preventing TNF from binding to TNF receptors
on cell surface membranes of target cells. The second
approach is to use monoclonal antibodies to bind and neutralize circulating cytokines.
Soluble TNF Receptors
Etanercept (Enbrel) is a genetically engineered, dimerized,
fusion protein composed of two TNF p75 receptors and an
IgG1:Fc portion. On the basis of early preclinical studies
showing that etanercept was sufficient to reverse the deleterious negative inotropic effects of TNF in vitro61 and in vivo,7
a series of phase I clinical studies was performed in patients
with moderate to advanced heart failure. These early shortterm studies in small numbers of patients showed improvements in quality of life, 6-minute walking distance, and LV
ejection performance after treatment with etanercept for up to
3 months.62,63 After this, two multicenter clinical trials using
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etanercept were initiated in patients with NYHA class II to IV
heart failure. The trial in North America, entitled Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE, n⫽900), and the trial in
Europe and Australia, entitled Research into Etanercept
Cytokine Antagonism in Ventricular Dysfunction (RECOVER, n⫽900), were both quality-of-life trials that used a
clinical composite as the primary end point. The clinical
composite score classifies patients as better, worse, or the
same after a clinical intervention, on the basis of the patient’s
and the physician’s assessment at the end of the study.64 Both
trials had parallel study designs but differed in the doses of
etanercept that were used in the two studies: RENAISSANCE
used doses of 25 mg twice a week (biw) and 25 mg three
times a week (tiw), whereas RECOVER used doses of 25 mg
once a week (qw) and 25 mg biw. A third trial that used the
pooled data from the RENAISSANCE (biw and tiw dosing)
and RECOVER (biw dosing only), termed Randomized
Etanercept Worldwide Evaluation (RENEWAL, n⫽1500),
had a primary end point of all-cause mortality and hospitalization for heart failure as the a primary end point. On the
basis of prespecified stopping rules, the trials were stopped
early after the Data Monitoring Safety Board deemed that is
was unlikely that the trials would show benefit on the primary
end points if the two trials were allowed to go to completion.3
Preliminary analysis of the data showed no benefit for
etanercept on the clinical composite end point in RENAISSANCE and RECOVER nor a benefit for etanercept
on all-cause mortality and heart failure hospitalization in
RENEWAL.3,64a However, in a post hoc analysis of hazard
ratios for death/worsening heart failure, patients taking the
biw dose of etanercept appeared to fare slightly better than
patients taking the qw dose of etanercept in RECOVER, with
hazard ratios for death/heart failure hospitalization of 0.87
and 1.01, respectively. In contrast, RENAISSANCE patients
receiving biw etanercept experienced a 1.21 risk of death/
heart failure hospitalization compared with the risk in patients
receiving placebo, whereas patients receiving the tiw dose
had a slightly worse hazard ratio of 1.23. These disparities in
trial findings are likely related to the different length of
follow-up in the two trials. Patients in RECOVER received
etanercept for a median time of 5.7 months, whereas patients
in RENAISSANCE received etanercept for 12.7 months. It
bears emphasis that these studies were stopped prematurely;
had they been allowed to continue to completion, the hazard
ratios may have been worse. On the basis of these findings,
the prescribing information for etanercept has been updated
and now suggests that physicians exercise caution in the use
of etanercept in patients with heart failure.
Monoclonal Antibodies
A second targeted approach that has been tried in clinical
heart failure trials is the use monoclonal antibodies directed
against a particular cytokine. Infliximab (Remicade) is a
chimeric monoclonal antibody consisting of a genetically
engineered murine Fab fragment (that binds human TNF)
fused to a human FC portion of human IgG1. Although
infliximab had been shown to be effective in Crohn’s disease
and rheumatoid arthritis, there are no published preclinical
nor phase I safety studies to support the use of this specific
agent in heart failure. The Anti-TNF␣ Therapy Against CHF
(ATTACH) was a phase II study in 150 patients with
moderate to advanced heart failure. The primary end point of
the ATTACH trial was the clinical composite score described
above.64 Patients were randomized to receive three separate
intravenous infusions of infliximab (5 or 10 mg/kg) at
baseline and at 2 and 4 weeks, followed by an assessment of
the clinical composite at 14 and 28 weeks. Analysis of the
completed trial data showed that there was a dose-related
increase in death and heart failure hospitalizations with
infliximab compared with placebo at 14 weeks (21% increase) and at 28 weeks (26% increase). By 38 weeks of
follow-up, 9 infliximab patients had died (2 in the 5 mg/kg
group and 7 in the 10 mg/kg group) compared with just one
death in the placebo group.4,64b On the basis of these findings,
the prescribing information for infliximab in rheumatoid
arthritis and Crohn’s disease now cautions against its use in
patients with heart failure.
Why Have Targeted Anti-TNF Therapies Failed in
Heart Failure Trials?
Given the wealth of preclinical data and early clinical studies
that have suggested a role for TNF antagonism in heart
failure, the negative results of the clinical trials have been
discouraging. This statement notwithstanding, analysis of the
aggregate clinical trial data permits some insight into why
these studies have been negative. It is important to recognize
that neither the trials with etanercept nor the trial with
infliximab was neutral (ie, no effect). Instead what was
consistently observed in both trials was a dose- and timedependent worsening of heart failure and/or worsening outcomes. Although one can never exclude “play of chance” as
a plausible explanation for the worsening clinical outcomes in
both trials, the dose- and time-dependent effects that were
observed in both trials argue against this possibility. However, there are two explanations that warrant further discussion. The first is that the biological agents that were used in
the trials had intrinsic toxicity, and the second is that TNF
antagonism has untoward effects in the setting of heart
failure. Regarding the first explanation, it bears emphasis that
infliximab exerts its effects, at least in part, by fixing
complement in cells that express TNF on the membrane. As
shown in Figure 7A, infliximab is directly cytotoxic to cells
expressing TNF on the membrane. Whereas this type of
biological action is beneficial in eliminating activated T cells
that have invaded the gastrointestinal mucosa of patients with
Crohn’s disease, it is likely to be overtly deleterious in the
setting of heart failure, wherein failing myocytes express
TNF on their cell membranes.65 Complement fixation in the
heart leads to sustained myocarditis as well as cardiac
myocyte lysis mediated by the complement membrane attack
complex.66 Cytokine binding proteins such as etanercept also
have intrinsic biological activity and, in certain settings, can
act as agonists for the cytokine that they bind.67 As a case in
point, in human studies, etanercept acts as a carrier protein
that stabilizes TNF and results in the accumulation of high
concentrations of immunoreactive TNF in the peripheral
circulation (Figure 7B).68 As shown in Figure 7C, TNF
Mann
Inflammatory Mediators and Heart Failure
995
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Figure 7. Biological properties of infliximab and etanercept. A, Infliximab (cA2
G1) is cytotoxic for cells that express
TNF on their cell membranes (TNF⫹),
whereas it is not cytotoxic for cells that
do not express TNF on their membranes
(SP2/O). The mechanism for the cytotoxic effects of infliximab was demonstrated using F(ab)2 fragments of infliximab, which lack the Fc domain and
therefore cannot fix complement. As
shown, the F(ab)2 fragment of infliximab
was not cytotoxic for TNF⫹ cells.83
Reproduced from Scallon BJ, Moore MA,
Trinh H, Knight DM, Ghrayeb J. Chimeric
anti-TNF-␣ monoclonal antibody cA2
binds recombinant transmembrane
TNF-␣ and activates immune effector
functions. Cytokine. 1995;7:251–259, by
permission of the International Cytokine
Society ©1995. B, Etanercept increases
the levels of immunoreactive TNF in the
peripheral circulation of human subjects
after intravenous endotoxin administration. As shown, high-dose etanercept (60
mg/m2) increased immunoreactive TNF
2
levels more than low-dose etanercept (10 mg/m ). Modified from Suffredini AF, Reda D, Banks SM, Tropea M, Agosti JM, Miller R.
Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration.
J Immunol. 1995;155:5038 –5045, by permission of the American Association of Immunologists ©1995. C, Kinetic analysis of TNF binding to etanercept using surface plasmon resonance biosensor technology (BIAcore assay84) is shown. Etanercept was exposed to 1000,
500, 250, 125, 62.5, 31.25, 16.63, 3.90, and 1.95 nmol/L TNF, and the kinetics of TNF binding were determined by the decay of the
light signal after peak binding to etanercept. The off rate of TNF from etanercept was determined to be 620 ms. Reproduced from
Frishman JI, Edwards CK III, Sonnenberg MG, Kohno T, Cohen AM, Dinarello CA. Tumor necrosis factor (TNF)-␣-induced interleukin-8
in human blood cultures discriminates neutralization by the p55 and p75 TNF soluble receptors. J Infect Dis. 2000;182:1722–1730, by
permission of the Infectious Diseases Society of America ©2000. D, Etanercept increases TNF bioactivity. Animals were inoculated with
bacteria, and levels of TNF bioactivity were measured at the indicated time points. TNF bioactivity peaked at 90 minutes after bacterial
inoculation but was undetectable at later time points. Mice treated with etanercept after bacterial inoculation showed a significant
reduction in the level of peak TNF bioactivity; however, as shown, TNF bioactivity was significantly prolonged by etanercept. Mice that
received etanercept after bacterial inoculation followed by an anti-TNF neutralizing antibody (TN3) had a shorter duration of TNF bioactivity. The arrow indicates the timing of the administration of the neutralizing anti-TNF antibody.85 Modified from Evans TJ, Moyes D,
Carpenter A, Martin R, Loetscher H, Lesslauer W, Cohen J. Protective effect of 55- but not 75-kD soluble tumor necrosis factor
receptor-immunoglobulin G fusion proteins in an animal model of gram-negative sepsis. J Exp Med. 1994;180:2173–2179, by permission of the Rockefeller University Press ©1994.
complexed to etanercept does not remain tightly bound but
dissociates with an extremely fast off rate (⬇620 ms).69 The
increase in the levels of TNF bound to etanercept and the
rapid off rates of TNF from etanercept can lead to an increase
in the duration of TNF bioactivity, as shown in Figure 7D.
Thus, in summary, panels B and D of Figure 7 show that
etanercept can, in certain settings, act as a “stimulating
antagonist.”67 Although the aforementioned biological effects
of etanercept might not be problematic in rheumatoid arthritis, wherein TNF is encapsulated within a joint space and
peripheral circulating TNF levels are relatively low (compared with heart failure) or are nonexistent,70 an increase in
the circulating levels of biologically active TNF in a patient
with heart failure might be expected to produce worsening
heart failure because of the known biological properties of
TNF (Table). And indeed, this may have been one of the
reasons that high doses of etanercept led to worsening clinical
outcomes in systemic sepsis.71
A second explanation for worsening heart failure in the
clinical trials is that TNF antagonism has deleterious effects in
the setting of heart failure. Several experimental studies have
suggested that physiological levels of TNF confer cytoprotective
responses in the heart during acute ischemic injury.72–74 Moreover, low physiological levels are likely to play an important role
in tissue remodeling and repair. Thus, one potential explanation
for the worsening heart failure observed in the targeted anti-TNF
trials (albeit speculative) is that our current targeted attempts to
antagonize TNF result in the loss of one or more of the beneficial
effects of TNF and that this loss of homeostasis results in
worsening of heart failure. Indeed, in our overly simplistic view
of heart failure, we tend to view molecules in absolute terms as
having either “good” or “bad” effects, with little or no consideration given to the potential for concurrent offsetting biological
effects. However, in many instances, molecules such as TNF
exert a spectrum of pleiotropic effects in the failing heart: some
beneficial and some potentially deleterious. Accordingly, TNF
antagonism might be expected to attenuate both the deleterious
and beneficial effects of TNF. The observation that TNF
antagonism provides short-term beneficial effects in heart failure
patients62,63 and yet results in worsening heart failure when used
chronically is entirely consistent with this point of view.
Immunomodulatory Strategies
An alternative approach to targeting specific components of
the inflammatory cascade is to use approaches that result in a
decrease in the systemic inflammatory response. Thus far,
two different approaches have been used in heart failure
studies: intravenous immunoglobulin (IVIG) and “immune
modulation therapy.”
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Intravenous Immunoglobulin
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Therapy with IVIG has been tried in a wide range of
immune-mediated disorders, such as Kawasaki’s syndrome,
dermatomyositis, and multiple sclerosis. Although the exact
mechanism of action of IVIG is not known, a number of
different mechanisms have been proposed, including Fc
receptor blockade, neutralization of autoantibodies, modulation of cytokine activity, and activation of an inhibitory Fc
receptor.75 On the basis of an initial report that IVIG was
beneficial in acute cardiomyopathy,76 Gullestad et al77 conducted a double-blind trial with IVIG for 26 weeks in 47
patients with moderate heart failure who were receiving
conventional therapy for heart failure, including ACE inhibitors and ␤-blockers. They observed that compared with
placebo, IVIG induced a marked rise in plasma levels of the
antiinflammatory mediators (IL-10 and IL-1 receptor antagonist) and that these changes were accompanied by a significant increase in LV ejection performance by ⬇10% and a
decrease in N-terminal proatrial natriuretic peptide levels.77
Thus, in that small study, immunomodulatory therapy with
IVIG was effective in patients with heart failure.
Immune Modulation Therapy
Immune modulation therapy uses a medical device (the
VC7000 Blood Treatment System, Vasogen Inc) to expose a
sample of blood to a combination of physiochemical stressors
ex vivo. The treated blood sample is then administered
intramuscularly along with local anesthetic into the same
patient from whom the sample is obtained. The physiochemical stresses to which the autologous blood sample is subjected
are known to initiate or facilitate apoptotic cell death. The
uptake of apoptotic cells by macrophages results in a downregulation of proinflammatory cytokines, including TNF,
IL-1␤, and IL-8, and an increase in production of the
antiinflammatory cytokines, including transforming growth
factor-␤ and IL-10.78,79 Recent studies have shown that
immune modulation therapy leads to a decrease in the
production of proinflammatory cytokines and a corresponding increase in antiinflammatory cytokines in human subjects.80 Given that an imbalance exists between proinflammatory and antiinflammatory cytokines in patients with heart
failure,39 immune modulation therapy may restore this balance more toward normal. In a recent trial using immune
modulation therapy in 73 patients with moderate heart failure,
the investigators noted that compared with the placebo group,
the group receiving immune modulation therapy experienced
significantly fewer hospitalizations (24 versus 41) and deaths
(1 versus 7). The decrease in event rate in the treatment arm
was also supported by improvements in quality of life and
NYHA clinical classification.81,81a Based on the encouraging
results of this pilot trial, a larger pivotal trial involving
immune modulation therapy is being planned.
Inflammatory Mediators and the Failing
Heart: Past, Present, and the
Foreseeable Future
In the present review, we have focused on the recent clinical
and experimental evidence suggesting that inflammatory
mediators play a role in disease progression in heart failure by
virtue of the direct toxic effects that these molecules exert on
the heart and the peripheral circulation. Indeed, pathophysiologically relevant concentrations of these molecules mimic
many aspects of the so-called heart failure phenotype in
experimental animals, including LV dysfunction, LV dilation,
activation of fetal gene expression, cardiac myocyte hypertrophy, and cardiac myocyte apoptosis (Table). Thus, analogous to the proposed role for neurohormones in heart failure,
inflammatory mediators represent another distinct class of
biologically active molecules that may contribute to the
progression of heart failure. Nonetheless, the early attempts
to translate this information to the bedside not only have been
disappointing but also have led to worsening heart failure in
many instances. Although one interpretation of these findings
is that inflammatory mediators are not viable targets in heart
failure, according to the arguments delineated above, the
countervailing point of view is that we simply have not
targeted proinflammatory mediators with agents that can be
used safely in the context of heart failure or that targeting a
single component of the inflammatory cascade is not sufficient in a disease as complex as heart failure. This latter
statement notwithstanding, it should also be recognized that
in the wake of the current success with ␤-blockers, no recent
clinical trials have been able to improve on conventional
therapy for heart failure. Accordingly, we may have reached
a therapeutic ceiling for the so-called neurohormonal approaches for treating heart failure. This having been said, is
there a foreseeable future for antiinflammatory strategies in
heart failure? Despite the inauspicious beginning with targeted antiinflammatory approaches, strategies that use small
molecules that have a broad spectrum of antiinflammatory
properties (eg, pentoxifylline, thalidomide [or its analogues],
and statins) and immunomodulatory strategies that activate
antiinflammatory pathways (eg, immune modulation therapy)
are currently being evaluated. As with all therapeutic approaches in heart failure, the only way to really answer the
question of whether broader spectrum antiinflammatory strategies will have any added value in heart failure, aside from
the empiric hand-waving of a few pundits and prophets, is
through well-designed clinical trials.
Acknowledgments
This work was supported by research funds from the Department of
Veterans Affairs and the NIH (P50 HL-O6H and RO1 HL-58081-01,
RO1 HL-61543-01, and HL-42250-10/10). The author would like to
apologize in advance to his colleagues whose work was not cited
because of imposed space limitations. The author would like to thank
Mary Helen Soliz for secretarial support and Dr Andrew I. Schafer
for his past guidance and support.
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Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future
Douglas L. Mann
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Circ Res. 2002;91:988-998
doi: 10.1161/01.RES.0000043825.01705.1B
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