MiniReview |
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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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 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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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.
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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.
| Models of Heart Failure From Cardiac Apoptosis |
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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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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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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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| Acknowledgments |
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Received February 9, 2000; accepted April 14, 2000.
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H. Oh, S. C. Wang, A. Prahash, M. Sano, C. S. Moravec, G. E. Taffet, L. H. Michael, K. A. Youker, M. L. Entman, and M. D. Schneider Telomere attrition and Chk2 activation in human heart failure PNAS, April 29, 2003; 100(9): 5378 - 5383. [Abstract] [Full Text] [PDF] |
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E. J. Su, C. L. Cioffi, S. Stefansson, N. Mittereder, M. Garay, D. Hreniuk, and G. Liau Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1429 - H1440. [Abstract] [Full Text] [PDF] |
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B. Nadal-Ginard, J. Kajstura, A. Leri, and P. Anversa Myocyte Death, Growth, and Regeneration in Cardiac Hypertrophy and Failure Circ. Res., February 7, 2003; 92(2): 139 - 150. [Abstract] [Full Text] [PDF] |
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J. Suzuki, E. Bayna, E. Dalle Molle, and W. Y. W. Lew Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats J. Am. Coll. Cardiol., February 5, 2003; 41(3): 482 - 488. [Abstract] [Full Text] [PDF] |
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G. Valen The basic biology of apoptosis and its implications for cardiac function and viability Ann. Thorac. Surg., February 1, 2003; 75(2): S656 - 660. [Abstract] [Full Text] [PDF] |
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J. R. Gonzalez-Juanatey, M. J. Iglesias, C. Alcaide, R. Pineiro, and F. Lago Doxazosin Induces Apoptosis in Cardiomyocytes Cultured In Vitro by a Mechanism That Is Independent of {alpha}1-Adrenergic Blockade Circulation, January 7, 2003; 107(1): 127 - 131. [Abstract] [Full Text] [PDF] |
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A. van der Laarse Hypothesis: troponin degradation is one of the factors responsible for deterioration of left ventricular function in heart failure Cardiovasc Res, October 1, 2002; 56(1): 8 - 14. [Abstract] [Full Text] [PDF] |
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J. Bartunek, M. Vanderheyden, M. W. M. Knaapen, W. Tack, M. M. Kockx, and M. Goethals Deoxyribonucleic acid damage/repairproteins are elevated in the failing human myocardium due to idiopathic dilated cardiomyopathy J. Am. Coll. Cardiol., September 18, 2002; 40(6): 1097 - 1103. [Abstract] [Full Text] [PDF] |
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H. L. Li, J. Suzuki, E. Bayna, F.-M. Zhang, E. Dalle Molle, A. Clark, R. L. Engler, and W. Y. W. Lew Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT1 receptors Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H461 - H467. [Abstract] [Full Text] [PDF] |
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K. Hayakawa, G. Takemura, M. Koda, Y. Kawase, R. Maruyama, Y. Li, S. Minatoguchi, T. Fujiwara, and H. Fujiwara Sensitivity to Apoptosis Signal, Clearance Rate, and Ultrastructure of Fas Ligand-Induced Apoptosis in In Vivo Adult Cardiac Cells Circulation, June 25, 2002; 105(25): 3039 - 3045. [Abstract] [Full Text] [PDF] |
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G. W. De Keulenaer, Y. Wang, Y. Feng, S. Muangman, K. Yamamoto, J. F. Thompson, T. G. Turi, K. Landschutz, and R. T. Lee Identification of IEX-1 as a Biomechanically Controlled Nuclear Factor-{kappa}B Target Gene That Inhibits Cardiomyocyte Hypertrophy Circ. Res., April 5, 2002; 90(6): 690 - 696. [Abstract] [Full Text] [PDF] |
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M. T. Santore, D. S. McClintock, V. Y. Lee, G. R. S. Budinger, and N. S. Chandel Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L727 - L734. [Abstract] [Full Text] [PDF] |
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A. Yndestad, J. Kristian Damas, H. Geir Eiken, T. Holm, T. Haug, S. Simonsen, S. S. Froland, L. Gullestad, and P. Aukrust Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure Cardiovasc Res, April 1, 2002; 54(1): 175 - 182. [Abstract] [Full Text] [PDF] |
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R. J. Scheubel, B. Bartling, A. Simm, R.-E. Silber, K. Drogaris, D. Darmer, and J. Holtz Apoptotic pathway activation from mitochondria and death receptors without caspase-3 cleavage in failing human myocardium: Fragile balance of myocyte survival? J. Am. Coll. Cardiol., February 6, 2002; 39(3): 481 - 488. [Abstract] [Full Text] [PDF] |
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D. S. McClintock, M. T. Santore, V. Y. Lee, J. Brunelle, G. R. S. Budinger, W.-X. Zong, C. B. Thompson, N. Hay, and N. S. Chandel Bcl-2 Family Members and Functional Electron Transport Chain Regulate Oxygen Deprivation-Induced Cell Death Mol. Cell. Biol., January 1, 2002; 22(1): 94 - 104. [Abstract] [Full Text] [PDF] |
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M. A. Fortuno, S. Ravassa, A. Fortuno, G. Zalba, and J. Diez Cardiomyocyte Apoptotic Cell Death in Arterial Hypertension: Mechanisms and Potential Management Hypertension, December 1, 2001; 38(6): 1406 - 1412. [Abstract] [Full Text] [PDF] |
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R.-P. Xiao {beta}-Adrenergic Signaling in the Heart: Dual Coupling of the {beta}2-Adrenergic Receptor to Gs and Gi Proteins Sci. Signal., October 16, 2001; 2001(104): re15 - re15. [Abstract] [Full Text] [PDF] |
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F. Qin, N. K. Rounds, W. Mao, K. Kawai, and C.-s. Liang Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets Cardiovasc Res, September 1, 2001; 51(4): 736 - 748. [Abstract] [Full Text] [PDF] |
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M. W.M. Knaapen, M. J. Davies, M. De Bie, A. J. Haven, W. Martinet, and M. M. Kockx Apoptotic versus autophagic cell death in heart failure Cardiovasc Res, August 1, 2001; 51(2): 304 - 312. [Abstract] [Full Text] [PDF] |
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I. M.C. Dixon Help from within: cardioprotective properties of hepatocyte growth factor Cardiovasc Res, July 1, 2001; 51(1): 4 - 6. [Full Text] [PDF] |
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J. D. Molkentin Calcineurin, Mitochondrial Membrane Potential, and Cardiomyocyte Apoptosis Circ. Res., June 22, 2001; 88(12): 1220 - 1222. [Full Text] [PDF] |
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