Circulation Research. 2000;86:1107-1113
(Circulation Research. 2000;86:1107.)
© 2000 American Heart Association, Inc.
Apoptosis and Heart Failure
A Critical Review of the Literature
Peter M. Kang,
Seigo Izumo
From the Cardiovascular Division, Beth Israel Deaconess Medical Center
and Harvard Medical School, Boston, Mass.
Correspondence to Seigo Izumo, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, SL-201, Boston, MA 02215. E-mail sizumo{at}caregroup.harvard.edu
Key Words: apoptosis heart failure treatment humans animals
 |
Introduction
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This MiniReview is part of a thematic series on
Apoptosis
in the Cardiovascular System, which includes the following
articles:
Apoptosis and Heart Failure: A Critical Review of the Literature
Vascular Cell Apoptosis in Remodeling, Restenosis, and Plaque
Rupture Apoptosis During Cardiovascular Development Myocyte
Apoptosis in Ischemic Heart Disease Endothelial Cell Apoptosis in
Angiogenesis and Vessel Regression
Richard Kitsis, Editor
When the concept of apoptosis was introduced in
the 1970s,1 it attracted only limited attention. However,
less than two decades ago, Horvitz and colleagues2 3 4
identified its essential genetic components in the roundworm,
Caenorhabditis elegans, and apoptosis emerged as a
significant research front. The explosion of knowledge that took place
is represented by the accumulation of >25 000 studies in
the last 5 years alone. It is now clear that apoptosis is an
important aspect of normal organ development and cellular regulation
and that it plays a role in a wide variety of
physiological and pathological conditions. However,
there is still much debate and controversy concerning the role of
apoptosis in heart failure. To address the issues of its
presence in, significance for, and overall contribution to heart
failure, we will review the currently available literature and then
discuss its implications for future research and treatment strategies
in heart failure.
 |
Evidence of Apoptosis in Animal and Human Models of
Heart Failure
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The etiology of heart failure involves multiple agents and
conditions,
5 but the progressive loss of cardiac myocytes
is one of the
most important pathogenic components. During the past few
years,
there has been accumulating evidence in both human and animal
models
suggesting that apoptosis may be an important mode of
cell death
during heart failure (Table 1

). Therefore, the possibility of
limiting
cardiac myocyte loss by inhibiting apoptosis has
potentially
important implications in the treatment of heart
failure.
The numerous animal models of heart failure encompass a spectrum of
species and a variety of apoptotic inducers.6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
These studies suggest that the rate of occurrence of apoptosis
can vary widely and depends on the model used and the area at risk
examined. For example, in acute ischemia and reperfusion,
apoptosis can be high as 14% in the area at
risk.25 In contrast, the rate of apoptosis
associated with chronic stimuli, such as pressure overload, is <1% in
nontransgenic models when measured by terminal
deoxynucleotidyl transferasemediated dUTP nick
end-labeling (TUNEL) staining.14 17 But even though the
rate of apoptosis in heart failure is relatively low in
absolute numbers, it is significantly higher than that in the normal
heart, which has essentially negligible baseline apoptosis.
In human heart failure, the data are limited to postmortem samples or
tissue samples from patients undergoing heart
transplantation.29 30 31 32 33 34 35 36 37 38 39 40 41 Although the initial studies
reported unrealistically high levels of apoptosis in failed
hearts (as much as 35%),40 41 more recent studies showed
apoptosis rates of <1% (TUNEL-positive cells) during heart
failure.31 35 38 The most common forms of heart failure
associated with apoptosis are idiopathic dilated
cardiomyopathy and ischemic
cardiomyopathy, but apoptosis has been
observed in other forms of heart failure as
well.36 39 41
 |
Problems With Interpreting the Presence of Apoptosis in
Heart Failure
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Despite the wealth of published data, there are still many
controversies
surrounding the presence and the significance of
apoptosis in
heart failure. These controversies stem largely
from the limitations
of the technique used to detect apoptosis
and the difficulties
in translating these findings to the ultimate
significance of
apoptosis in heart failure.
Acute insults, such as myocardial infarction and
ischemia/reperfusion, and chronic conditions, such as
ischemic and dilated cardiomyopathies, have
been linked to increased apoptotic cell death in human and
animal hearts.38 40 42 But not all models of heart failure
are associated with apoptosis43 44 45 46 47 48 49 (Table 2
). Notably, the presence of
apoptosis in inflammatory myocarditis is a controversial issue.
In viral myocarditis, increased TUNEL staining is associated mostly
with infiltrating mononuclear cells or noncardiac myocytes rather than
cardiac myocytes.44 45 46 49 In contrast, autoimmune
myocarditis is associated with increased TUNEL staining in cardiac
myocytes as well as in lymphocytes.50 Although more
studies are needed, it is likely that the presence of apoptosis
depends on the model system.
The specificity of TUNEL staining, which is the most widely used method
to detect apoptosis in the heart, has also been challenged.
Using the electron microscopic TUNEL method, Fujiwaras
group51 52 showed that positive TUNEL staining is
associated not only with apoptotic myocytes but also with
oncotic (necrotic) myocytes or even viable myocytes that are undergoing
DNA repair. Because the rate of apoptosis is generally very low
in normal heart as well as in heart failure, a high false-positive rate
severely limits the interpretation of TUNEL-positive cells. On the
other hand, there are other limitations of the TUNEL staining that will
significantly underestimate the true incidence of apoptosis and
thus obscure its significance in heart failure. For example, because
the apoptotic process is transient, the window of opportunity
for detecting apoptotic cells by use of TUNEL staining will
also be transient. In lymphocytes, the TUNEL-positive period is
generally <12 hours. If the same holds true for cardiac myocytes,
TUNEL staining may markedly underestimate the true prevalence of
apoptosis in heart failure, which usually occurs over many
months or years. Moreover, the rate of apoptosis may be
variable and may depend on the disease stage. Most of the human
studies to detect apoptosis have been performed in patients
undergoing heart transplant, who are at the advanced stage of the
disease. It is possible that samples obtained from these patients
represent a "burnt-out" state, characterized by minimal
ongoing apoptosis, much like a battlefield days after the
fighting has ended.
The definition of apoptosis, compared with necrosis, also has
been a subject of controversy. Necrosis is an unregulated process
leading to cell demise, but apoptosis is ordered and
regulated,. Therefore, apoptosis can be, at least in theory,
prevented or inhibited if intervention occurs at an early stage. A
number of studies have attempted to distinguish apoptosis and
necrosis under various conditions with the use of several
methodologies.17 31 53 Because necrosis, in contrast to
apoptosis, is characterized by inflammation and the release of
intracellular contents that are toxic to neighboring cells,
significantly different consequences on cardiac
hemodynamics may result. However, at this time, it is
unclear whether necrosis and apoptosis are 2 distinct and
independent cell death pathways. It has been suggested that the
difference between apoptosis and necrosis is in the level of
intracellular ATP present and that the cell that is undergoing
apoptosis can be made to undergo necrosis by intracellular ATP
depletion.54 55 Because the consequence of cell death by
either mode is ultimately cell loss, the most important issue from a
therapeutic standpoint is whether the cell loss can be attenuated.
Thus, rather than a strict distinction between apoptosis and
necrosis, whether cell death ultimately can be inhibited or not may
prove to be a more important distinction from the clinical
standpoint.
Because of the limitations associated with TUNEL staining and the
difficulties of interpreting these findings (however well done), the
use of TUNEL alone to detect the presence of apoptosis is not
sufficient to define the role of apoptosis in heart failure. We
need more studies using in vitro models of cardiac myocyte
apoptosis to decipher and to understand the molecular mechanism
of apoptosis in cardiac myocytes. In addition, we need
"interventional studies" using transgenic and cardiac-specific gene
knockout mice models to study the consequences of genetic manipulation
of proapoptotic and antiapoptotic genes in vivo. These
should be complemented by studies in larger animal models (eg, pigs or
dogs) that can mimic human clinical conditions much better than murine
models, as well as by pharmacological studies to modulate
apoptosis.
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Models of Heart Failure From Cardiac Apoptosis
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Recently, animal models of heart failure incorporating transgenic
technology
have confirmed that myocyte apoptosis itself is
sufficient to
induce heart failure.
6 Kitsis et
al
6 generated transgenic
mice with cardiac-specific
overexpression of ligand-activatable
cysteine aspartate proteinase
(caspase-8), which is an artificial
(or engineered) fusion protein
consisting of the FK506 binding
protein and the catalytic domain of
caspase-8. Transgenic mice
expressing this construct appeared normal at
birth, but administration
of the divalent dimerizer FK1012
activated caspase-8 and -3,
resulting in overwhelming cardiac
myocyte apoptosis and rapid
death of the animal. Perhaps not
surprisingly, even in the absence
of a dimerizer, adult mice with high
expression of the protein
manifest spontaneous cardiac myocyte
apoptosis, leading over
time to a lethal dilated
cardiomyopathy. These changes were
ameliorated by a
broad-spectrum caspase inhibitor (R. Kitsis,
personal
communication, 2000). Although it is not clear whether
endogenous
caspase-8 is an important regulator of
apoptosis in heart, the
study of Kitsis et al
6
nevertheless demonstrates that the induction
of apoptosis can
be achieved in the heart. It also shows that
slow induction of
apoptosis alone can result in dilated
cardiomyopathy.
Another mouse model of heart failure uses cardiac-specific knockout of
gp130, a common subunit of the interleukin-6 family of cytokine
receptors that have been shown to promote cell survival in the presence
of an apoptotic stimulus in vitro.9 Under baseline
conditions, these mice showed a grossly normal phenotype with
normal cardiac structure and function. However, when gp130 knockout
mice were exposed to acute pressure overload by surgical constriction
of the transverse aorta, they developed significant cardiac
apoptosis (
34%), and >90% died by dilated
cardiomyopathy in a few weeks.9 In
contrast, normal wild-type mice exposed to similar pressure overload
developed compensatory cardiac hypertrophy without heart
failure. Of particular interest is that aortic-banded gp130 knockout
mice did not develop hypertrophy. Because gp130 has been
shown to provide important survival signals in the cardiac myocyte
during cardiac hypertrophy via
cardiotrophin-1,56 this model provides important clues to
the relationship between hypertrophy and apoptosis.
For example, for adaptive cardiac hypertrophy to occur in
response to mechanical stress, it is necessary to have
antiapoptotic or survival factors, such as gp130, present
in heart. The notion that cardiac hypertrophy is a
favorable adaptation to stress and that hypertrophied cells can be more
resistant to an apoptotic stimulus is also supported by
other transgenic models of cardiac hypertrophy.
Overexpression of calcineurin confers a protective effect on cardiac
myocytes both in vitro and in vivo when they are exposed to
apoptotic stimuli.57 Also, cardiac
hypertrophy by overexpression of insulin-like growth
factor-1 in animals has been shown to limit infarct size by limiting
apoptotic cell death.12 19
On the other hand, the overexpression of heterotrimeric G proteins,
such as Gq
or Gs
, may
promote apoptosis in cardiac myocytes.7 8 11 For
example, transgenic mice with overexpression of
G
q signaling develop
compensatory hypertrophy at baseline. However, when
transgenic females become pregnant, they develop lethal dilated
cardiomyopathy, resembling human peripartum
cardiomyopathy, within 1 week after
delivery.11 TUNEL staining of the heart revealed markedly
increased levels of apoptosis (
26%). Also,
Gs
overexpression results in increased
sensitivity to apoptotic stimulation and leads to
cardiomyopathy.7 This was confirmed by
blocking the ß-adrenergic receptor, which prevented myocyte damage,
decreased cardiac apoptosis, and preserved cardiac function in
Gs
transgenic mice.8 In addition,
other important hypertrophic signaling molecules, such as
angiotensin II, have also been shown to promote
apoptosis in vitro,58 and several studies show
that administration of angiotensin-converting enzyme
inhibitors blocks cardiac apoptosis in
vivo.17 21
These models of heart failure in mice demonstrate that
apoptosis does occur during heart failure and could play a
significant role in the development of heart failure in certain
settings. However, whether hypertrophy renders cardiac
myocytes more sensitive or resistant to apoptosis is
still controversial. Some hypertrophic signaling factors, such as
cardiotrophin-1 via gp130, insulin-like growth factor-1 via
phosphoinositide-3 kinase, and calcineurin via the
nuclear factor of activated T cells, seem to be protective. On
the other hand, hypertrophic signaling via heterotrimeric G proteins
and angiotensin II seems to render cardiac myocytes more
sensitive to apoptosis. These findings are important because
they provide possible strategies to modulate cardiac apoptosis.
However, we believe further studies, especially during the transition
from compensated hypertrophy to heart failure, are needed
to better understand the complex and delicate balance that exists among
hypertrophy, apoptosis, and heart failure.
 |
Regulation of Cardiac Apoptosis
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The major apoptotic pathway is initiated by the release of
cytochrome
c from mitochondria in response to an
apoptotic stimulus. Released
cytochrome
c, in the
presence of dATP, forms an activation complex
with apoptotic
protein-activating factor-1 and caspase-9 that
activates
downstream caspases to execute the final morphological
and biochemical
alterations.
59 60 61 62 63 This pathway is
tightly regulated
by a group of antiapoptotic proteins, such
as Bcl-2, and
proapoptotic proteins, such as Bax
64 65 ; further
regulation
occurs downstream by various inhibitors of
caspases.
66 There
is recent evidence to suggest that
cardiac myocytes also use
a mitochondria-dependent apoptotic
pathway.
67 68 69 Cytosolic
cytochrome
c and the
activation of caspases have been observed
in both human and animal
models of heart failure.
10 27 34 The
level of Bcl-2
is upregulated soon after acute coronary occlusions,
especially
in the salvageable myocardium,
53 70 71 but is
decreased
after chronic heart failure by pressure
overload.
14 Also, the
overexpression of Bcl-2 in the heart
effectively reduces myocardial
reperfusion injury by reducing cardiac
myocyte apoptosis.
72 Moreover, some studies
suggest that the balance between Bcl-2/Bax
may be important in the
increased rate of apoptosis in cardiac
myocytes.
10 14 18 23 These findings are supported by the
reversal of the
Bcl-2/Bax ratio in the heart after left
ventricular assist device
placement.
29
It has been suggested that the cardiac myocyte could also use an
alternative apoptotic pathway that activates downstream
caspases via "death receptors" (eg, Fas, tumor necrosis factor
[TNF] receptor) and caspase-8.32 37 Expression of the
death receptor Fas is upregulated in cardiac myocytes during myocardial
ischemia and heart failure,23 25 37 53 and
increased levels of soluble Fas ligand and TNF-
have been reported
in patients with end-stage heart failure.73 Also, in
immune-mediated cardiomyopathies, cardiac
apoptosis is associated with an augmented Fas/FasL
system.50 However, cardiac-specific overexpression of both
TNF-
and FasL did not result in increased cardiac myocyte
apoptosis.47 49 Therefore, we speculate that
although a death receptormediated pathway may be important in certain
situations, notably in immune-mediated heart failure, this may not be
the main pathway in more common forms of heart failure, such as
ischemic and dilated cardiomyopathy.
 |
Is There a Potential for Antiapoptotic Therapy for
Heart Failure?
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Several strategies can be used to inhibit apoptosis in
heart,
and various agents and factors have been shown to be effective
in
experimental models.
74 For example, caspase
inhibitors significantly
decrease apoptosis in the
area at risk, with subsequent reduction
in infarct size in rat hearts
during experimentally induced
ischemia and
reperfusion.
16 24 Furthermore, the long-term beneficial
effects
of angiotensin-converting enzyme
inhibitors and carvedilol in
the treatment of heart failure
may involve, at least in part,
inhibition of cardiac
apoptosis.
17 21 25
Even though the therapeutic targeting of apoptotic pathways has
potential in the treatment of heart failure, several important
questions still need to be answered. First, it has not yet been shown
whether inhibition of apoptosis could delay or prevent the
development of heart failure. It is possible that inhibiting
apoptosis may simply result in the activation of another mode
of cell death, such as necrosis, which may have more deleterious
effects on neighboring cells and ultimately a worse outcome. Although
the early studies on animal models of heart failure have been
encouraging, the long-term consequences of inhibiting apoptosis
in the heart are not known. Second, the safety of antiapoptotic
therapy has not been tested. Apoptosis is needed for the normal
functioning of other cell systems, such as the immune system, and an
excessive inhibition of apoptosis is associated with lymphoma
or autoimmune disorders. Therefore, the chronic systemic inhibition of
apoptosis may have significant deleterious consequences in
noncardiac organs. Third, antiapoptotic therapy for heart
failure may not apply to all types of heart failure. We speculate that
an antiapoptotic strategy for heart failure due to persistent
pressure overload will remain controversial for a while, because
chronic and complete inhibition of apoptosis may be very
difficult to achieve with the current repertoire of drugs. The role of
antiapoptotic therapy in heart failure associated primarily
with inflammation (eg, viral myocarditis) may also remain controversial
because the removal of virally infected cells is likely to be a
necessary step toward recovery. The most ideal conditions for
antiapoptotic intervention, in our opinion, occur in transient
and acute insults, such as reperfusion. During reperfusion, cardiac
myocyte apoptosis occurs at a high rate during a defined time
period; thus, a short treatment period may be highly effective.
Moreover, a short therapeutic course has the additional benefit of
minimizing the possible deleterious side effects arising in other organ
systems.
 |
Conclusion
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It is clear that apoptosis plays an important role in a
variety
of physiological and pathological states.
However, in the cardiovascular
system, we have only
begun to clarify the role of apoptosis
and to start exploring
the therapeutic potential associated
with its inhibition. Still more
work is necessary to understand
the molecular mechanisms that govern
these processes and the
significance of apoptosis in heart
failure. Apoptosis must be
demonstrated by multiple criteria,
not just TUNEL staining alone.
Genetic interventional studies should be
explored further by
use of mouse models, but pharmacological studies
using large
animal models should be encouraged. The initial analytical
work
must be carried out in well-defined experimental frameworks
that
are tissue-targeted and time specific, with clear quantitative
end
points. Only then will we be able to conduct meaningful
human studies
to answer whether the inhibition of apoptosis
in heart failure
will translate into clinical benefit.
 |
Acknowledgments
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This study was supported by an individual National Research
Service
Award Fellowship (Dr Kang) and by National Institutes of Health
grant
R01 AG17008 (Dr Izumo). We thank Ellen Gower for editorial
assistance
and Hiroki Aoki for helpful discussions.
Received February 9, 2000;
accepted April 14, 2000.
 |
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