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(Circulation Research. 2000;86:1107.)
© 2000 American Heart Association, Inc.

MiniReview

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

Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 
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 colleagues^{2 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

Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 
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.

View this table: [in this window] [in a new window]   Table 1. Heart Failure Models Associated With Increased Apoptosis in Heart

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 transferase–mediated 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

Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 
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 apoptosis^{43 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.

View this table: [in this window] [in a new window]   Table 2. Heart Failure Models Not Associated With Increased Apoptosis in Heart

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, Fujiwara’s group^{51 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

Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 
Recently, animal models of heart failure incorporating transgenic technology have confirmed that myocyte apoptosis itself is sufficient to induce heart failure.⁶ Kitsis et al⁶ 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 al⁶ 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 G_q or G_s, 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, G_s 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 G_s 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

Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 
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 receptor–mediated 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?

Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 
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

Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 
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

 
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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Top Introduction Evidence of Apoptosis in... Problems With Interpreting the... Models of Heart Failure... Regulation of Cardiac Apoptosis Is There a Potential... Conclusion References

 

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