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Physiology 22: 56-64, 2007; doi:10.1152/physiol.00033.2006
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Physiology, Vol. 22, No. 1, 56-64, February 2007
© 2007 Int. Union Physiol. Sci./Am. Physiol. Soc.

REVIEW

Decompensation of Cardiac Hypertrophy: Cellular Mechanisms and Novel Therapeutic Targets

Abhinav Diwan and Gerald W. Dorn, II

Center for Molecular Cardiovascular Research, University of Cincinnati, Cincinnati, Ohio, dorngw{at}ucmail.uc.edu


   Abstract
 
Cardiac hypertrophy leads to heart failure, and both conditions can ultimately prove lethal. Here, traditional and novel mechanisms relating hypertrophy and heart failure are described at the physiological, cellular, and molecular levels. The rational application of these mechanistic considerations to therapeutics targeting hypertrophy and heart failure is discussed.


   Basic Concepts of Compensatory and Decompensated Cardiac Hypertrophy
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 Basic Concepts of Compensatory...
Cardiac Myocyte Death: A...
 Cardiomyocyte Necrosis in...
 Apoptosis in Hypertrophy...
 Autophagy in Heart Failure:...
 Regression of Pathological...
 Summary
 References
 
Hypertrophy [from the Greek hyper (over) and trophy (growth)] of the human heart is a morphological clinical diagnosis defined by increased myocardial mass. Premortem, the diagnosis is usually based on calculated echocardiographic or magnetic resonance imaging estimates of left ventricular mass. Postmortem, the pathological diagnosis is based on direct measurements of gravimetric heart weight. Notably, there is no functional aspect to the diagnosis of cardiac hypertrophy, and it can occur in hearts with normal, supernormal, or depressed cardiac performance. Thus "hypertrophy" per se does not necessarily imply disease, since conditioned athletes can develop cardiac enlargement and increased myocardial mass with no adverse consequences. This exercise-induced or "physiological" hypertrophy is distinguished from pathological stress-induced hypertrophy at the molecular, cellular, functional, and prognostic levels (22) and, except where specifically stated, is not the topic of this review.

Determining whether cardiac hypertrophy exists in individual patients is a medical imperative because of irrefutable epidemiological evidence that it constitutes an important independent risk factor for death (41, 49, 80). The same studies also indicate that cardiac hypertrophy with normal cardiac function tends to progress over time to depressed cardiac function, described as "hypertrophy decompensation," and clinically resulting in the syndrome of heart failure (broadly defined as any condition in which the forward output of the heart is insufficient to meet the metabolic demands of the organism). Heart failure itself is a highly lethal disease with a 5 year mortality in treated patients that is worse than that of many malignancies (38) and that affects 5 million adults in the United States alone. Thus the human suffering and societal burden of heart failure is staggering (79), and the possibility that prevention of hypertrophy decompensation could reduce the prevalence of heart failure has provided a strong impetus for mechanistic studies of the decompensation process and prompted attempts to develop potential means of preventing hypertrophy or its pathological sequelae. Indeed, primary or secondary prevention of hypertrophy, as with treatment of hypertension using vasodilators or neurohormonal inhibitors, can improve clinical outcomes (57).

At the cellular level, cardiac hypertrophy is the consequence of an increase in cardiac myocyte size. Since cardiac myocytes have little or no capacity for cellular proliferation, their only means of growth is by cellular enlargement. Since cardiac failure most commonly results from an insufficiency of myocardium (as opposed to an abnormal increase in metabolic demand, as in "high output failure"), it is not surprising that cardiomyocyte hypertrophy is the dominant cellular response to virtually all forms of hemodynamic overload or myocardial injury. Although it seems intuitively obvious that growing more myocardium could produce functional adaptation in a syndrome caused by myocardial insufficiency, specific hemodynamic benefits can be demonstrated through application of physical principles in the context of known biological events. These principles explain hypertrophic compensation as an adaptive mechanism that preserves cardiac ejection performance by normalizing wall stress (FIGURE 1Go). The Laplace relationship establishes that wall stress (which at ventricular end systole can be considered as cardiac "afterload") of a thin-walled sphere is determined by intraluminal pressure, chamber size, and wall thickness:


Figure 1
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  		FIGURE 1. Development and progression of decompensated chamber hypertrophy
Compensated cardiac hypertrophy manifests as an increase in ventricular wall thickness (h’ > h, wall thickness), characterized by cardiomyocyte growth in response to hemodynamic stress and/or myocardial injury. Neurohormonal activation transduces development of hypertrophy. Cardiomyocyte death provokes transition to cardiomyopathic dilation (r’ > r, radius of the ventricular cavity) and wall thinning (h’’ < h’). Inset: the inverse relationship between ventricular wall stress and contractile performance, with progression of compensated hypertrophy to cardiomyopathic decompensation.

 

Formula

where {alpha} is wall stress, p is intracavitary pressure, r is the internal radius of the chamber, and h is the thickness of the chamber walls. Thus, in a situation such as hypertension where increased pressure results in increased stress on the heart, a reactive increase in wall thickness (FIGURE 1Go, h’) can normalize wall stress and preserve systolic function (29). This is the basis for previous designations of reactive cardiac hypertrophy as "compensatory." However, as discussed below, recent studies in which pressure overload hypertrophy has been inhibited through genetic modification of hypertrophy signaling pathways suggest that "compensatory" hypertrophy may not actually be essential to functional compensation, at least in the short term (24, 34, 35, 71).

Long-term maladaptive remodeling of reactive hypertrophy is associated with progressive ventricular dilation. The consequences of cardiac enlargement (r’) and wall thinning (h’’) on wall stress are also shown in FIGURE 1Go: When the ratio r’/h’’ increases, so does wall stress, despite constant intracavitary pressure. This geometrical increase in wall stress generates its own hemodynamic stress on the heart, further stimulating already overloaded hypertrophy signaling pathways and tipping the balance from a cell growth response to one of cell death. Once these processes have progressed to this stage, i.e., decompensation, loss of cardiac myocytes and their replacement by fibrous tissue rapidly diminishes contractile performance in "end-stage" cardiomyopathy, leading to irreversible functional deterioration, intractable heart failure, and ultimately death.


   Cardiac Myocyte Death: A Cause and Consequence of Hypertrophy Decompensation
Top
 Basic Concepts of Compensatory...
 Cardiac Myocyte Death: A...
Cardiomyocyte Necrosis in...
 Apoptosis in Hypertrophy...
 Autophagy in Heart Failure:...
 Regression of Pathological...
 Summary
 References
 
Although stress-mediated myocardial hypertrophy is a complex condition associated with numerous adverse consequences, including alterations in intercellular matrix leading to interstitial fibrosis, loss of ß-adrenergic receptor responsiveness, and metabolically unfavorable changes in contractile protein isoforms, the defining irreversible cellular event in hypertrophy decompensation is cardiomyocyte degeneration and death, detected histologically in early cardiomyopathy as "cardiomyocyte drop-out." It is a biological irony that the same neurohormones that stimulate "compensatory" cardiomyocyte hypertrophy in response to hemodynamic stress also contribute to cell death (2, 20, 21). Whereas the exact pathway to cell death varies with physiological context, there are three clearly defined pathologically and mechanistically distinct modes of death: necrosis (oncosis), apoptosis, and autophagy (54) (FIGURE 2Go). There is clinico-pathological evidence for all three forms of death in end-stage human cardiomyopathy (33, 72). Thus cardiomyocyte replacement and myocardial fibrosis are characteristic of all forms of pathological hypertrophy and progress in parallel with functional decompensation (33, 45, 72). Presaging actual cardiac myocyte death is ultra-structural evidence of myocyte degeneration with loss of sarcomeric organization and an increase in cytoskeletal elements in terminal failing human left ventricular myocardium. Likewise, progressive left ventricular remodeling in severe aortic valvular stenosis exhibits myocyte degeneration and fibrosis that correlates with worsening systolic function (33). In this study, morphological evidence for all three cell death pathways (oncosis or necrosis, apoptosis, and autophagy) was seen in hypertrophied myocardium with worsening ventricular systolic function, i.e., during the decompensation phase.


Figure 2
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  		FIGURE 2. Modes of cell death in hypertrophy
Diagram depicting three modes of death: 1) apoptosis or cell suicide, 2) necrosis or oncosis, and 3) autophagy.

 

   Cardiomyocyte Necrosis in Decompensated Heart Failure: A Stake Through the Heart
Top
 Basic Concepts of Compensatory...
 Cardiac Myocyte Death: A...
 Cardiomyocyte Necrosis in...
Apoptosis in Hypertrophy...
 Autophagy in Heart Failure:...
 Regression of Pathological...
 Summary
 References
 
Oncosis (from the Greek onkos for mass or tumor) was a term coined by Von-Recklinghausen to describe the characteristic cellular swelling and karyolysis observed in some forms of cellular death. Subsequent studies identified oncosis as a form of ischemic necrosis (from nekros, Greek for dead body) in various model systems (54, 89). Cardiac myocyte necrosis is the oldest postulated means of cell death in decompensating hypertrophy leading to cardiomyopathy, and an intriguing mechanistic hypothesis was developed to causally link cardiomyocyte hypertrophy and death: the "ischemic core" hypothesis. The notion is that hypertrophy, which in human heart failure can increase cardiomyocyte cross-sectional area threefold, simply overwhelms the physiological and physical limits of oxygen delivery to the center of the myocyte. Oxygen diffusion through cell cytoplasm (largely water) is invariant, as is the physiological range of oxygen tension that forms the diffusion gradient through the cell. Thus, when the cross-sectional area of a cardiac myocyte exceeds the distance across which oxygen can diffuse down its concentration gradient from adjacent capillaries, mitochondria at the core of the cardiomyocyte become ischemic, with resulting diminished ATP-generating ability and contractile depression (81). Additionally, cardiac hypertrophy is associated with a relative decrease in myocardial capillary density because capillary angiogenesis does not occur in parallel with hypertrophying myocytes (37), resulting in an absolute reduction in myocardial oxygen delivery per unit of myocardium. Finally, perivascular and interstitial fibrosis produce a physical diffusion barrier for delivery of nutrients and oxygen.

The necrotic core mechanism is intellectually appealing but has been difficult to prove. Supportive evidence has been generated in a murine model of inducible activated Akt/protein kinase B (74). The Akt-signaling pathway is an important mediator of non-pathological ("physiological") myocardial growth, as induced by growth factor pathways and exercise (21). However, sustained activation of Akt signaling through forced expression of myristoylated (activated) AKT provoked progressive left ventricular dilation with systolic dysfunction, i.e., the development of dilated cardiomyopathy and heart failure (58). Development of cardiomyopathy should not have occurred if Akt-induced hypertrophy is physiological, unless the hypertrophy itself causes secondary pathology. Recently, conditional myocardial expression of activated Akt caused reversible hypertrophy at 2 weeks but a progressive and irreversible cardiomyopathy with decreased myocardial capillary density and increased fibrosis after 6 weeks (74). Notably, coronary angiogenesis was enhanced during the compensated acute hypertrophic phase but was reduced during the period of pathological remodeling and hypertrophy decompensation. Additionally, inhibition of angiogenesis using a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. The association of decreased vascularity and progression to decompensated cardiomyopathy in a model of excessive "physiological" hypertrophy supports the necrotic core hypothesis. The converse experiment, determining whether enhanced angiogenesis can ameliorate the transition of compensated to decompensated hypertrophy, has not yet been reported.


   Apoptosis in Hypertrophy Decompensation: Suicide is not Painless
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 Basic Concepts of Compensatory...
 Cardiac Myocyte Death: A...
 Cardiomyocyte Necrosis in...
 Apoptosis in Hypertrophy...
Autophagy in Heart Failure:...
 Regression of Pathological...
 Summary
 References
 
Although necrosis is cell death caused by intrinsic factors, cells can also choose suicide via inducible cell death programs. The most completely studied form of programmed cell death in heart failure is apoptosis (from the Greek apo, meaning away from, and ptosis, meaning falling), a term originally used to describe the series of programmed death events that culminates in the autumnal falling of leaves from decidual trees. There are numerous examples of clinical cardiomyopathies and experimental models of heart failure or hypertrophy decompensation in which apoptosis is strikingly increased and likely plays a significant pathophysiological role (5, 10, 23, 26, 50, 62, 64, 82).

Apoptosis is a generalized but highly regulated cell response that is essential to eliminate unnecessary tissue that develops during embryonic differentiation (such as the regression of inter-digital webs of the hands) (52) and that limits the proliferation of abnormal or damaged cells that could otherwise form malignant tumors (83). Cells undergoing apoptosis are distinguished morphologically from oncosis and other forms of cell death by characteristic nuclear chromatin condensation and nuclear fragmentation that forms dense "apoptotic bodies" (56). This process of protein and chromatin fragmentation into small packages that can be engulfed by scavenger cells provides for elimination of a dying cell without provocation of a potentially injurious inflammatory response. Thus apoptosis under normal conditions is a cleaner way of eliminating non-desirable cells and avoids or preempts cellular swelling, rupture, and secondary infiltration of inflammatory cells that occur with necrotic cell death.

As is proper for a tissue without any significant capacity for regeneration (12, 65), apoptosis is extremely rare in the normal myocardium, with reported rates of 1 apoptotic cardiomyocyte in 10,000–100,000 (75). However, the rate of cardiac myocyte apoptosis can increase by orders of magnitude in the human heart diseases associated with cardiomyocyte drop-out, such as dilated and ischemic cardiomyopathies (62, 64), hypertrophic heart disease (33), and arrhythmogenic right ventricular dysplasia (55). There are two distinct apoptosis signaling pathways that can be induced in heart failure: the death receptor and mitochondrial pathways. The general mechanisms of cardiac myocyte apoptosis have been the subject of many excellent reviews (14, 26, 53) and, therefore, are only summarized here. Briefly, in the death receptor pathway (also known as the extrinsic pathway), cell death is initiated by cytokine binding to membrane receptors, such as TNF superfamily receptors or Fas. Activated receptors oligomerize and form a death signaling complex containing FADD (Fas associated death domain-containing protein), which recruits caspase 8 and initiates the apoptotic cascade of caspase proteases that culminates in systematic degradation of intracellular proteins and oligonucleosomal DNA cleavage. In contrast, the mitochondrial pathway (also known as the intrinsic pathway) is initiated when outer mitochondrial membrane permeabilization permits cytochrome c release into the cytoplasm, resulting in formation of the apoptosome complex with Apaf-1, which recruits caspase 9 and initiates the caspase cascade.

" Cardiac myocyte necrosis is the oldest postulated means of cell death in decompensating hypertrophy leading to cardiomyopathy..."

Molecular links between hypertrophic and apoptotic pathways have been described for both the death receptor and the mitochondrial pathways. In the death receptor pathway, there are cyto-protective anti-apoptotic factors that antagonize the death receptor response. Ablation of one such protective "life receptor," that for the cytokine signal transducer of interleukin-6 family proteins, Gp130, had no effects on normal cardiac function but caused a dilated cardiomyopathy and massive cardiac myocyte apoptosis after induction of pressure overload by acute microsurgical transverse aortic coarctation in mice (36). This striking result revealed the potentially catastrophic consequences when absence of a critical prosurvival pathway leads to disinhibition of cardiomyocyte apoptosis during development of pressure overload hypertrophy. Absence of a phenotype in nonstressed mice also indicates that cardiomyocyte apoptosis is somehow stimulated in cardiac myocytes by the hypertrophic process, which supports the notion that an apoptosis gene program is induced by cardiac hypertrophy.

Inducible pro-apoptotic genes have been detected in pressure overload hypertrophy of mice and humans (86) as well as in genetic mouse models of hypertrophy (6). In particular, details are emerging supporting a prominent role for the BH3-only, Bcl2 family protein, Nix, as a mediator of apoptotic hypertrophy decompensation. When transgenic expression of the G{alpha}q signaling protein, which transduces signals from epinephrine, angiotensin II, and endothelin receptors (20), was used to produce a model of reactive hypertrophy independent of hemodynamic overload, pathological hypertrophy developed (16) with provokable apoptosis in response to various forms of physiological stress (2, 70). In this model, cardiomyocyte apoptosis is unambiguously the cause of transitioning from compensated hypertrophy to decompensated heart failure, as inhibition of apoptosis by pharmacological caspase inhibition prevents cardiomyopathic degeneration (32). Transcriptome analysis of G{alpha}q hearts revealed several components of a putative inducible cardiomyocyte death program and led to identification of the Bcl-2 family member, Nix.

The Bcl-2 family proteins are a broadly expressed and evolutionarily conserved group of apoptosis modulators (1). Based on structural features, they are separated into "multidomain" and "BH3-only" classes. The multidomain proapoptotic Bcl-2 proteins, Bax and Bak, are the essential pore-forming proteins that lead to mitochondrial outer membrane permeabilization and induction of the intrinsic apoptosis signaling cascade. Their many antiapoptotic counterparts, including prototypical Bcl2 and Bcl-xl, inhibit this process by hetero-dimerizing with their pro-apoptotic relatives. In contrast to the multi-domain proteins, the principal role of the subclass of BH3 domain-only proteins appears to be to regulate the multidomain proteins by sensing stress signals and undergoing increased expression, activation, or mitochondrial translocation (76). Thus the multidomain proteins are the effectors, and the BH3-only proteins the sensors and regulators, of mitochondrial pathway apoptosis. Nix, an inducible cardiac-expressed BH3-only protein, is transcriptionally upregulated in hypertrophies resulting from forced increases in G{alpha}q signaling, experimental pressure overload hypertrophy, and human hypertensive heart disease (86). Analysis of the transcriptional events leading to Nix induction has revealed an important role for PKC (28), which is activated in reactive hypertrophy (21). Transgenic overexpression of Nix was sufficient to produce an apoptotic cardiomyopathy, and apoptotic cardiomyopathies can be rescued by coexpression of a Nix dominant inhibitor lacking the mitochondrial targeting domain (77, 86). We consider that Nix and other factors that may be similarly induced during cardiomyocyte hypertrophic growth sensitize the myocyte to apoptosis, especially when normal protective factors are diminished.


   Autophagy in Heart Failure: What’s on the Menu?
Top
 Basic Concepts of Compensatory...
 Cardiac Myocyte Death: A...
 Cardiomyocyte Necrosis in...
 Apoptosis in Hypertrophy...
 Autophagy in Heart Failure:...
Regression of Pathological...
 Summary
 References
 
Like apoptosis, autophagy (Greek autos, meaning, self and phagein, meaning to eat) is an essential normal cellular process that, in heart failure, goes awry (8). Within the normal homeostatic processes of cell protein replacement, autophagy is the primary mechanism for degradation of large organelles and long-lived proteins through the lysosomal pathway, whereas nonlysosomal degradation of shorter lived and/or regulatory proteins occurs largely via the ubiquitin-proteasome system (9, 15, 25, 47, 48, 60). The histological hallmark of autophagy is the double membrane delimited autophagosome, which contains proteins destined for degradation and achieves this by fusing with lysosomes (60). Since cardiac hypertrophy is accomplished through massive alterations in normal cardiomyocyte protein homeostasis, with accelerated protein breakdown and synthesis (13), normal proteolytic processes are accelerated. The rate of myocardial protein synthesis is measurably higher than baseline within 6 h of induction of pressure overload and continues to be increased throughout the period of ongoing hypertrophic growth (39). Although protein turnover (synthesis and breakdown) is increased during hypertrophy, it has been suggested that autophagy is actually diminished in response to aortic stenosis and isoproteronol infusion in animal models, possibly reflecting an anti-catabolic effect during active hypertrophy (17, 69).

Initially described as a cell survival mechanism in starvation (9, 46), autophagy has recently received a great deal of attention as a mechanism of cell death in other several clinical disorders, including heart failure. Schaper et al. (72) observed autophagosome-like cytoplasmic inclusions in cardiomyocytes from patients with heart failure. These cells also exhibited sarcomeric degeneration, suggesting the possibility that the inclusions represented "autophagic" sarcomeric protein. Frequent autophagic vacuoles staining positively for ubiquitin have also been observed in the myocardium of patients with severe aortic stenosis (33). Remarkably, ubiquitin positivity increased 12-fold in the myocardium of severe aortic stenosis patients with severe left ventricular systolic dysfunction (left ventricular ejection fraction of <30%) compared with patients with preserved ventricular function. Autophagic cell death is also prevalent in human and hamster cardiomyopathies (59, 73) and a model of diphtheria toxin-induced heart failure (3). Finally, mutations in, and deletion of, the gene encoding for lamp2, a critical lysosomal membrane protein, are associated with accumulations of autophagic vacuoles in liver, muscle, and heart cells that mimic the human cardiomyopathic phenotype in Danon disease (15, 78, 84). Together, these observations suggest that autophagy in cardiomyocytes is an essential component of the normal process for renewal of cellular proteins but that conditions of greatly accelerated protein turnover, as in hypertrophied cardiac myocytes that are subjected to additional hemodynamic or metabolic stress, can perturb this normal function and result in cell death (48).


   Regression of Pathological Hypertrophy: Through the Looking Glass, Alice
Top
 Basic Concepts of Compensatory...
 Cardiac Myocyte Death: A...
 Cardiomyocyte Necrosis in...
 Apoptosis in Hypertrophy...
 Autophagy in Heart Failure:...
 Regression of Pathological...
Summary
 References
 
In designing therapeutics that might prevent the progression from compensated hypertrophy to decompensated heart failure, it would be attractive to target one or more of the mechanisms of cell death, i.e., necrosis, apoptosis, and autophagy (FIGURE 3Go). This is likely to be difficult, however, since the pathways for each are distinct, and apoptosis and autophagy have important physiological roles in nonmyocytes, if not in myocytes themselves. Thus it may be more effective to target hypertrophy itself rather than its progression. One approach would be to modify hypertrophy so that the benefits of increased myocardial mass are not diminished by the unique functional and molecular characteristics of reactive or "pathological" hypertrophy. For example, if hypertrophied myocardium had the characteristics of the athlete’s heart ("physiological hypertrophy"), then progression to heart failure would not be expected to occur. Indeed, endurance training by swimming was demonstrated by Scheuer (67) to be beneficial in rodent heart failure over 30 years ago. Conversely, even intermittent pressure overload (mimicking the intermittent hemodynamic stress of exercise/endurance training) results in development of hypertrophy with the typical pathological features (68). Molecular approaches designed to recapitulate physiological hypertrophy via growth factor pathways or their downstream mediators have shown some promise in experimental models of cardiac disease (44).


Figure 3
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  		FIGURE 3. Therapeutic strategies to prevent decompensated heart failure
Hemodynamic stress and myocardial injury provoke development of compensated hypertrophy via neurohormonal signaling, which can be inhibited by neurohormonal antagonist. Cardiomyocyte death provokes transition to decompensated hypertrophy, which is a therapeutic target for antiapoptosis therapies. Attempts to provoke physiological hypertrophy antagonize cardiomyocyte death. Genetic and pharmacological strategies targeted at stimulating antihypertrophic pathways in a novel therapeutic approach to reverse compensated hypertrophy before its irreversible progression to decompensated heart failure.

 
Another approach, previously thought to be problematic, is to eliminate reactive hypertrophy altogether. Although the Laplace relationship demonstrates how myocardial hypertrophy can normalize ventricular wall stress, recent data have strongly suggested that hypertrophy of the type that develops in response to hemodynamic overload ("pathological hypertrophy"), may not be either necessary or desirable for functional compensation. Multiple gene or pharmacological manipulations that interfere with critical hypertrophy signaling pathways have suggested that cardiac function is retained after pressure overloading when the hypertrophic response is inhibited (24, 34, 35, 71). Murine models with inhibition of G{alpha}q signaling or ablation of the catecholaminergic dopamine ß-hydroxylase gene exhibit attenuated hypertrophy but are protected from adverse remodeling and functional deterioration under conditions of pressure overload where ventricular wall stress is elevated (24). This contrasts with the situation in normal mice studied under the same experimental conditions, in which development of reactive hypertrophy tends to normalize wall stress but was nevertheless associated with cardiac enlargement and contractile dysfunction.

If myocardial hypertrophy is not essential for acute functional compensation, then efforts directed at preventing hypertrophy are attractive. Clinically, neuro-hormonal inhibition with adrenergic, angiotensin, or endothelin antagonists can partially reverse cardiac hypertrophy via multiple mechanisms, including altered loading conditions (66).

With increased understanding of hypertrophy signaling pathways (27), refined approaches are being developed to inhibit pathological hypertrophy, while preserving the beneficial aspects of these signaling pathways (31, 61). For example, whether signaling through a particular pathway is deleterious may depend on the time or duration of activation, such as in the PI3K/Akt pathway, wherein temporally limited signaling is essential for physiological growth (21), but chronic activation can lead to cardiomyopathy (63). Likewise, activation of specific arms of individual signaling cascades may be preferable, such as the MAP-kinase pathways wherein MEK1-ERK signaling seems to promote compensatory hypertrophy (11), but activation of p38 and JNK kinases leads to decompensated cardiomyopathy (51, 88). Indeed, prevention of hypertrophy by inhibition of certain targets such as FAK-focal adhesion kinase, which transduces integrin signaling sensing biomechanical stress and leads to hypertrophy, may be deleterious (18). The increasingly detailed knowledge of interactive hypertrophy signaling pathways provides a conceptual framework that suggests multiple possible strategies to inhibit hypertrophy but also suggests the potential for promiscuous effects of individual therapies based on inter-pathway cross talk.

A novel approach targeting reactive hypertrophy that is receiving increasing attention is activation of those intrinsic pathways that negatively regulate hypertrophic growth, i.e., endogenous inhibitors of hypertrophy. Some of these anti-hypertrophic signaling pathways are constitutively active in normal myocardium, such as glycogen synthase kinase GSK3ß (4), class II histone deactyleases (HDACII) (87), phospholipase A2 (30), thioredoxin (85), and caveolin 3 (42). During periods of hemodynamic stress, the activity of these pathways is suppressed, thus disinhibiting hypertrophic signaling. Other anti-hypertrophic pathways are normally silent but are strongly induced by hemodynamic overload, such as cAMP early repressor (ICER), MCIP-1, ANP/BNP, SOCS-3, and tend to restrain the hypertrophic response in a classical negative feedback loop (31). One such inducible anti-hypertrophic factor, which targets the hypertrophic effects of protein kinase C (19), is PICOT (PKC interacting cousin of thioredoxin) (40). PICOT is induced in pressure overload hypertrophy, and its forced expression in the myocardium reduced pressure overload hypertrophy by ~50%, while significantly enhancing myocardial systolic performance. Another potentially attractive target for inhibiting hypertrophy is histone acetylation/deacetylation byhi-stone acetyl transferase (HAT) and histone deacetylase (HDAC) enzyme system (7). These enzymes modulating the effects of multiple transcription factors and are key regulators of stress-induced pathological myocardial growth, and inhibition of HDACs with broad-spectrum inhibitors has prevented development of pressure overload hypertrophy (43).


   Summary
Top
 Basic Concepts of Compensatory...
 Cardiac Myocyte Death: A...
 Cardiomyocyte Necrosis in...
 Apoptosis in Hypertrophy...
 Autophagy in Heart Failure:...
 Regression of Pathological...
 Summary
References
 
A great deal of progress has been made in elucidating the mechanisms of reactive cardiac hypertrophy, and multiple pathways leading to adverse structural and functional remodeling have been delineated. Cardiomyocyte hypertrophy is the nearly universal response to functional cardiac insufficiency, but it may not be essential to physiological adaptation, and it clearly sets the stage for cardiomyocyte death from oncosis, apoptosis, or autophagy. Loss of cardiomyocytes and contractile dysfunction of those that survive are the underlying mechanisms for cardiomyopathy development and progression of heart failure. Strategies directed at modulating myocardial hypertrophy, reversing cardiac remodeling, and preventing cardiomyocyte death through targeting of relevant hypertrophy/death signaling pathways or activation of endogenous antihypertrophic mechanisms are promising avenues to addressing the problem of heart failure.


   Acknowledgments
 
This research was supported by National Heart, Lung, and Blood Institute Grants HL-59888, HL-69779, HL-77101, and HL-80008, and the Veterans’ Administration


   References
Top
 Basic Concepts of Compensatory...
 Cardiac Myocyte Death: A...
 Cardiomyocyte Necrosis in...
 Apoptosis in Hypertrophy...
 Autophagy in Heart Failure:...
 Regression of Pathological...
 Summary
 References
 

  1. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 281: 1322–1326, 1998.[Abstract/Free Full Text]
  2. Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, Chien KR, Brown JH, Dorn GW. Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci USA 95: 10140–10145, 1998.[Abstract/Free Full Text]
  3. Akazawa H, Komazaki S, Shimomura H, Terasaki F, Zou Y, Takano H, Nagai T, Komuro I. Diphtheria toxin-induced autophagic cardiomyocyte death plays a pathogenic role in mouse model of heart failure. J Biol Chem 279: 41095–41103, 2004.[Abstract/Free Full Text]
  4. Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN. Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 99: 907–912, 2002.[Abstract/Free Full Text]
  5. Anversa P, Leri A, Beltrami CA, Guerra S, Kajstura J. Myocyte death and growth in the failing heart. Lab Invest 78: 767–786, 1998.[Web of Science][Medline]
  6. Aronow BJ, Toyokawa T, Canning A, Haghighi K, Delling U, Kranias E, Molkentin JD, Dorn GW. Divergent transcriptional responses to independent genetic causes of cardiac hypertrophy. Physiol Genomics 6: 19–28, 2001.[Abstract/Free Full Text]
  7. Backs J, Olson EN. Control of cardiac growth by histone acetylation/deacetylation. Circ Res 98: 15–24, 2006.[Abstract/Free Full Text]
  8. Baehrecke EH. Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol 6: 505–510, 2005.
  9. Baehrecke EH. Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol 6: 505–510, 2005.
  10. Bing OH, Brooks WW, Robinson KG, Slawsky MT, Hayes JA, Litwin SE, Sen S, Conrad CH. The spontaneously hypertensive rat as a model of the transition from compensated left ventricular hypertrophy to failure. J Mol Cell Cardiol 27: 383–396, 1995.[Web of Science][Medline]
  11. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J 19: 6341–6350, 2000.[CrossRef][Web of Science][Medline]
  12. Bugaisky L, Zak R. Cellular growth of cardiac muscle after birth. Tex Rep Biol Med 39: 123–138, 1979.[Web of Science][Medline]
  13. Carabello BA. Concentric versus eccentric remodeling. J Card Fail 8: S258–S263, 2002.[CrossRef][Web of Science][Medline]
  14. Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res 95: 957–970, 2004.[Abstract/Free Full Text]
  15. Cuervo AMAutophagy: in sickness and in health. Trends Cell Biol 14: 70–77, 2004.[CrossRef][Web of Science][Medline]
  16. D’Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB, Dorn GW. Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA 94: 8121–8126, 1997.[Abstract/Free Full Text]
  17. Dammrich J, Pfeifer U. Cardiac hypertrophy in rats after supravalvular aortic constriction. II Inhibition of cellular autophagy in hypertrophying cardiomyocytes. Virchows Arch B Cell Pathol Incl Mol Pathol 43: 287–307, 1983.[Web of Science][Medline]
  18. Dimichele LA, Doherty JT, Rojas M, Beggs HE, Reichardt LF, Mac CP, Taylor JM. Myocyte-restricted focal adhesion kinase deletion attenuates pressure overload-induced hypertrophy. Circ Res 99: 636–645, 2006.[Abstract/Free Full Text]
  19. Dorn GW. Containing hypertrophy with a PICOT fence. Circ Res 99: 228–230, 2006.[Free Full Text]
  20. Dorn GW, Brown JH. Gq signaling in cardiac adaptation and maladaptation. Trends Cardiovasc Med 9: 26–34, 1999.[CrossRef][Web of Science][Medline]
  21. Dorn GW, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 115: 527–537, 2005.[CrossRef][Web of Science][Medline]
  22. Dorn GW, Robbins J, Sugden PH. Phenotyping hypertrophy: eschew obfuscation. Circ Res 92: 1171–1175, 2003.[Free Full Text]
  23. Elsasser A, Suzuki K, Schaper J. Unresolved issues regarding the role of apoptosis in the pathogenesis of ischemic injury and heart failure. J Mol Cell Cardiol 32: 711–724, 2000.[CrossRef][Web of Science][Medline]
  24. Esposito G, Rapacciuolo A, Naga Prasad SV, Takaoka H, Thomas SA, Koch WJ, Rockman HA. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 105: 85–92, 2002.[Abstract/Free Full Text]
  25. Field ML, Clark JF. Inappropriate ubiquitin conjugation: a proposed mechanism contributing to heart failure. Cardiovasc Res 33: 8–12, 1997.[Abstract/Free Full Text]
  26. Foo RS, Mani K, Kitsis RN. Death begets failure in the heart. J Clin Invest 115: 565–571, 2005.[CrossRef][Web of Science][Medline]
  27. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65: 45–79, 2003.[CrossRef][Web of Science][Medline]
  28. Galvez AS, Brunskill EW, Marreez Y, Benner BJ, Regula KM, Kirschenbaum LA, Dorn GW. Distinct pathways regulate proapoptotic nix and BNip3 in cardiac stress. J Biol Chem 281: 1442–1448, 2006.[Abstract/Free Full Text]
  29. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56: 56–64, 1975.[Web of Science][Medline]
  30. Haq S, Kilter H, Michael A, Tao J, O’Leary E, Sun XM, Walters B, Bhattacharya K, Chen X, Cui L, Andreucci M, Rosenzweig A, Guerrero JL, Patten R, Liao R, Molkentin J, Picard M, Bonventre JV, Force T. Deletion of cytosolic phospholipase A2 promotes striated muscle growth. Nat Med 9: 944–951, 2003.[CrossRef][Web of Science][Medline]
  31. Hardt SE, Sadoshima J. Negative regulators of cardiac hypertrophy. Cardiovasc Res 63: 500–509, 2004.[Abstract/Free Full Text]
  32. Hayakawa Y, Chandra M, Miao W, Shirani J, Brown JH, Dorn GW, Armstrong RC, Kitsis RN. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 108: 3036–3041, 2003.[Abstract/Free Full Text]
  33. Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klovekorn WP, Schaper J. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation 107: 984–991, 2003.[Abstract/Free Full Text]
  34. Hill JA, Karimi M, Kutschke W, Davisson RL, Zimmerman K, Wang Z, Kerber RE, Weiss RM. Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation 101: 2863–2869, 2000.[Abstract/Free Full Text]
  35. Hill JA, Rothermel B, Yoo KD, Cabuay B, Demetroulis E, Weiss RM, Kutschke W, Bassel-Duby R, Williams RS. Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. J Biol Chem 277: 10251–10255, 2002.[Abstract/Free Full Text]
  36. Hirota H, Chen J, Betz UA, Rajewsky K, Gu Y, Ross J Jr, Muller W, Chien KR. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97: 189–198, 1999.[CrossRef][Web of Science][Medline]
  37. Hudlicka O, Brown M, Egginton S. Angiogenesis in skeletal and cardiac muscle. Physiol Rev 72: 369–417, 1992.[Free Full Text]
  38. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 112: e154–e235, 2005.[Free Full Text]
  39. Imamura T, McDermott PJ, Kent RL, Nagatsu M, Cooper G, Carabello BA. Acute changes in myosin heavy chain synthesis rate in pressure versus volume overload. Circ Res 75: 418–425, 1994.[Abstract/Free Full Text]
  40. Jeong D, Cha H, Kim E, Kang M, Yang DK, Kim JM, Yoon PO, Oh JG, Bernecker OY, Sakata S, Le TT, Cui L, Lee YH, Kim dH, Woo SH, Liao R, Hajjar RJ, Park WJ. PICOT inhibits cardiac hypertrophy and enhances ventricular function and cardiomyocyte contractility. Circ Res 99: 307–314, 2006.[Abstract/Free Full Text]
  41. Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram. Prevalence, incidence, and mortality in the Framingham study. Ann Intern Med 71: 89–105, 1969.[Abstract/Free Full Text]
  42. Koga A, Oka N, Kikuchi T, Miyazaki H, Kato S, Imaizumi T. Adenovirus-mediated overexpression of caveolin-3 inhibits rat cardiomyocyte hypertrophy. Hypertension 42: 213–219, 2003.[Abstract/Free Full Text]
  43. Kong Y, Tannous P, Lu G, Berenji K, Rothermel BA, Olson EN, Hill JA. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation 113: 2579–2588, 2006.[Abstract/Free Full Text]
  44. Konhilas JP, Watson PA, Maass A, Boucek DM, Horn T, Stauffer BL, Luckey SW, Rosenberg P, Leinwand LA. Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Circ Res 98: 540–548, 2006.[Abstract/Free Full Text]
  45. Krayenbuehl HP, Hess OM, Monrad ES, Schneider J, Mall G, Turina M. Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement. Circulation 79: 744–755, 1989.[Abstract/Free Full Text]
  46. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature 432: 1032–1036, 2004.[CrossRef][Medline]
  47. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6: 463–477, 2004.[CrossRef][Web of Science][Medline]
  48. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest 115: 2679–2688, 2005.
  49. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322: 1561–1566, 1990.[Abstract]
  50. Li Z, Bing OH, Long X, Robinson KG, Lakatta EG. Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 272: H2313–H2319, 1997.[Abstract/Free Full Text]
  51. Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, Saffitz J, Chien K, Xiao RP, Kass DA, Wang Y. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci USA 98: 12283–12288, 2001.[Abstract/Free Full Text]
  52. Lockshin RA, Zakeri Z. Programmed cell death and apoptosis: origins of the theory. Nat Rev Mol Cell Biol 2: 545–550, 2001.[CrossRef][Web of Science][Medline]
  53. MacLellan WR, Schneider MD. Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res 81: 137–144, 1997.[Abstract/Free Full Text]
  54. Majno G, Joris I. Apoptosis, oncosis, necrosis. An overview of cell death. Am J Pathol 146: 3–15, 1995.[Abstract]
  55. Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 335: 1190–1196, 1996.[Abstract/Free Full Text]
  56. Martelli AM, Zweyer M, Ochs RL, Tazzari PL, Tabellini G, Narducci P, Bortul R. Nuclear apoptotic changes: an overview. J Cell Biochem 82: 634–646, 2001.[CrossRef][Web of Science][Medline]
  57. Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J, Sussex B, Probstfield J, Yusuf S. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 104: 1615–1621, 2001.[Abstract/Free Full Text]
  58. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, Rosenzweig A. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem 277: 22896–22901, 2002.[Abstract/Free Full Text]
  59. Miyata S, Takemura G, Kawase Y, Li Y, Okada H, Maruyama R, Ushikoshi H, Esaki M, Kanamori H, Li L, Misao Y, Tezuka A, Toyo-Oka T, Minatoguchi S, Fujiwara T, Fujiwara H. Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor. Am J Pathol 168: 386–397, 2006.[Abstract/Free Full Text]
  60. Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation in mammalian cells. Cell Struct Funct 27: 421–429, 2002.[CrossRef][Web of Science][Medline]
  61. Morisco C, Sadoshima J, Trimarco B, Arora R, Vatner DE, Vatner SF. Is treating cardiac hypertrophy salutary or detrimental: the two faces of Janus. Am J Physiol Heart Circ Physiol 284: H1043–H1047, 2003.[Free Full Text]
  62. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335: 1182–1189, 1996.[Abstract/Free Full Text]
  63. O’Neill BT, Abel ED. Akt1 in the cardiovascular system: friend or foe? J Clin Invest 115: 2059–2064, 2005.
  64. Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P. Apoptosis in the failing human heart. N Engl J Med 336: 1131–1141, 1997.[Abstract/Free Full Text]
  65. Oparil S, Bishop SP, Clubb FJ Jr. Myocardial cell hypertrophy or hyperplasia. Hypertension 6: III38–III43, 1984.
  66. Parmley WW. Evolution of angiotensin-converting enzyme inhibition in hypertension, heart failure, and vascular protection. Am J Med 105: 27S–31S, 1998.[Medline]
  67. Penpargkul S, Scheuer J. The effect of physical training upon the mechanical and metabolic performance of the rat heart. J Clin Invest 49: 1859–1868, 1970.[Web of Science][Medline]
  68. Perrino C, Prasad SV, Mao L, Noma T, Yan Z, Kim HS, Smithies O, Rockman HA. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest 116: 1547–1560, 2006.[CrossRef][Web of Science][Medline]
  69. Pfeifer U, Fohr J, Wilhelm W, Dammrich J. Short-term inhibition of cardiac cellular autophagy by isoproterenol. J Mol Cell Cardiol 19: 1179–1184, 1987.[CrossRef][Web of Science][Medline]
  70. Sakata Y, Hoit BD, Liggett SB, Walsh RA, Dorn GW. Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation 97: 1488–1495, 1998.[Abstract/Free Full Text]
  71. Sano M, Schneider MD. Still stressed out but doing fine: normalization of wall stress is superfluous to maintaining cardiac function in chronic pressure overload. Circulation 105: 8–10, 2002.[Free Full Text]
  72. Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Friedl A, Bleese N. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 83: 504–514, 1991.[Abstract/Free Full Text]
  73. Shimomura H, Terasaki F, Hayashi T, Kitaura Y, Isomura T, Suma H. Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J 65: 965–968, 2001.[CrossRef][Medline]
  74. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115: 2108–2118, 2005.[CrossRef][Web of Science][Medline]
  75. Soonpaa MH, Field LJ. Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res 83: 15–26, 1998.[Free Full Text]
  76. Strasser A. The role of BH3-only proteins in the immune system. Nat Rev Immunol 5: 189–200, 2005.[CrossRef][Web of Science][Medline]
  77. Syed F, Odley A, Hahn HS, Brunskill EW, Lynch RA, Marreez Y, Sanbe A, Robbins J, Dorn GW. Physiological growth synergizes with pathological genes in experimental cardiomyopathy. Circ Res 95: 1200–1206, 2004.[Abstract/Free Full Text]
  78. Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D, Lullmann-Rauch R, Janssen PM, Blanz J, von Figura K, Saftig P. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406: 902–906, 2000.[CrossRef][Medline]
  79. Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, Zheng ZJ, Flegal K, O’Donnell C, Kittner S, Lloyd-Jones D, Goff DC Jr, Hong Y, Adams R, Friday G, Furie K, Gorelick P, Kissela B, Marler J, Meigs J, Roger V, Sidney S, Sorlie P, Steinberger J, Wasserthiel-Smoller S, Wilson M, Wolf P. Heart disease and stroke statistics: 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113: e85–e151, 2006.[Free Full Text]
  80. Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart J 141: 334–341, 2001.[CrossRef][Web of Science][Medline]
  81. Vatner SF. Reduced subendocardial myocardial perfusion as one mechanism for congestive heart failure. Am J Cardiol 62: 94E–98E, 1988.[CrossRef][Medline]
  82. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, Kitsis RN. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 111: 1497–1504, 2003.[CrossRef][Web of Science][Medline]
  83. Wyllie AH. Apoptosis (the 1992 Frank Rose Memorial Lecture). Br J Cancer 67: 205–208, 1993.[Web of Science][Medline]
  84. Yamamoto A, Morisawa Y, Verloes A, Murakami N, Hirano M, Nonaka I, Nishino I. Infantile autophagic vacuolar myopathy is distinct from Danon disease. Neurology 57: 903–905, 2001.[Abstract/Free Full Text]
  85. Yamamoto M, Yang G, Hong C, Liu J, Holle E, Yu X, Wagner T, Vatner SF, Sadoshima J. Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy. J Clin Invest 112: 1395–1406, 2003.[CrossRef][Web of Science][Medline]
  86. Yussman MG, Toyokawa T, Odley A, Lynch RA, Wu G, Colbert MC, Aronow BJ, Lorenz JN, Dorn GW. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med 8: 725–730, 2002.[Web of Science][Medline]
  87. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110: 479–488, 2002.[CrossRef][Web of Science][Medline]
  88. Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, Michael LH, Overbeek PA, Schneider MD. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat Med 6: 556–563, 2000.[CrossRef][Web of Science][Medline]
  89. Zong WX, Thompson CB. Necrotic death as a cell fate. Genes Dev 20: 1–15, 2006.[Abstract/Free Full Text]



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