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In recent years myocyte loss due to apoptosis has gained increasing attention in the field of cardiovascular research, as myocyte apoptosis was observed in several disease states suggesting a potential pathophysiological role. Whereas initial studies were mostly observational verifying the occurrence of apoptotic myocytes in the heart, increasingly efforts are being made to disentagle the intracellular mechanisms that induce or inhibit myocyte apoptosis. As other chapters of this book deal with the more general aspects of apoptosis, the scope of this article will be limited to summarize current knowledge of the role of apoptosis in myocardial disease and the regulatory mechanisms known to be involved in myocyte apoptosis. [ABSTRACT FROM AUTHOR]

The identification and description of an intrinsic program of regulated cellular suicide or apoptosis was originally obtained from morphological analyses in developmental biology (76, 77). This program exists in all multicellular organisms, and genetic analyses in the nematode Caenorhabditis elegans identified three ced-genes (for C. elegans death) as basal, highly conserved components of this program, see (39, 57). In mammals, several structural and functional homologs of these ced-encoded proteins are involved in the apoptosis regulating complex formation at the outer mitochondrial membrane (Fig. 1), the apoptosome (56, 124), such as Apaf-1 (for "apoptosis protease activating factor") or proteins of the Bcl-2 family (see chapter I.2.2). Another important discovery from C. elegans genetics was the identification of interleukin-lß-converting enzyme (ICE or caspase-1) as a functional homolog of the ced-3 gene product. This discovery triggered the identification of a whole cascade of caspases (for "cysteine-containing aspartic acid proteases", see chapter I.3.1). This cascade is involved in the execution phase of apoptosis (164), and one source for activating the cascade is the mitochondrial apoptosome (Fig. 1). [ABSTRACT FROM AUTHOR]

A large array of cardiac diseases such as hypertensive heart disease and cardiac remodeling after myocardial infarction display significant gender-based differences (1, 2, 3). In this context it has been shown that during the process of aging cardiac number and diameter vary significantly between men and women. While cardiac myocytes of male patients tend to develop hypertrophy and polyploidy, cardiac myocytes of female patients remain consistent over time in terms of size and number of nuclei (4). The underlying mechanisms of this process remain to be elucidated. However, it is remarkable that the incidence of cardiac disease in female gender reveals a significant increase after the onset of menopause (5). Therefore it has been hypothesized that the decline of ovarian sex hormones after the onset of menopause, in particular estrogens, play an important role in the pathogenesis of cardiac disease in women. The role of estrogen in the pathogenesis of this process is currently under investigation (6-11). The influence of estrogen on the development of cardiac diseases can be divided in systemic and direct effects on the cardiovascular system. Systemic effects include the influence of sex hormones on lipid and insulin metabolism (12, 13). Furthermore, it has become evident that estrogens display a variety of genomic and non-genomic effects on cardiovascular tissues that may modulate the respective phenotype of these tissues. Two different estrogen receptors have been identified so far, estrogen receptor α and estrogen receptor β. These two subtypes differ in ligand binding as well as in DNA binding properties (14-18). [ABSTRACT FROM AUTHOR]

As summarized in this volume, most if not all cardiac cell types entertain the complex machinery of programmed cell death. Specifically, histochemical and molecular studies document beyond any doubt that cardiac myocytes, endothelial as well as vascular smooth muscle cells may undergo apoptosis. Moreover, death receptors, pro- and antiapoptotic factors as well as enzymatic cascades that -if activated-result in digestion of critical cellular structures have been localized to these cells. The stimuli that force cardiac cells into programmed death are also well characterized and include ischemia and/or reoxygenation, pressure overload or extensive stretching, or, finally, excessive stimulation with neurohormones or free radicals, just to name a few. While we are just at the beginning to understand these phenomena, a series of new questions emerges that asks for the appropriate integration of apoptosis in the pathophysiology of cardiac disease. [ABSTRACT FROM AUTHOR]

Apoptosis is considered as a form of physiological cell death, characterized by chromatin condensation, cytoplasmatic blebbing and DNA fragmentation. It plays a key role during development, homeostasis, and several diseases including cardiovascular disorders. Apoptosis occurs through the activation of a cell-intrinsic suicide program. The activation of the cell suicide program is regulated by many different signals that originate from both the intracellular and extracellular milieu ( 1 ). Experimental evidence suggests that exaggerated apoptosis may account for the loss of cardiomyocytes in heart failure. Furthermore, several factors intrinsic and extrinsic to the cardiomyocytes have been suggested as potential candidates to trigger apoptosis. [ABSTRACT FROM AUTHOR]

Chronic congestive heart failure, initiated by ischemic or hypertensive damage of the myocardium, can continue to worsen over months or years, despite the absence of clinically apparent acute events. Electron microscopic studies using myocardial specimen obtained from failing human hearts (1) and hearts of dogs with experimental heart failure (2) have clearly established the existence of cardiomyocyte apoptosis. Thus, it has been hypothesized that progressive cell loss by myocyte apoptosis may accelerate the natural course of congestive heart failure. Activation of neurohormonal mechanisms including the beta adrenergic system has been suggested to induce myocyte apoptosis and, thus, to promote the course of heart failure. [ABSTRACT FROM AUTHOR]

Apoptosis was first introduced into biology in a seminal paper by a group of pathologists studying cell population regulation (1). In this paper, the authors described a form of cell death marked by its singularity, a unique morphology and resolution without apparent "traces" (e.g., inflammation) in the tissue of origin. These features of cell death were contrasted to various forms of cell death by necrosis, due to noxious stimuli leading to cell membrane disruption, swelling, disintegration, cell-content leakage and local inflammation. Featuring prominently in the apoptotic process are the "apoptotic bodies" (fragments of dense DNA surrounded by an apparently intact plasma membrane), DNA condensation and fragmentation (the latter noted as "ladder" when separated on DNA-gel electrophoresis). The apoptosis phenotype has been later on associated with "programmed cell death" (PCD) described first in the nematode, C. elegance, where genetically specified deletions of cells during development followed a highly timed activation of specific genes (ced-3/4) (2). It is now quite common to use apoptosis and PCD interchangeably; in this review, apoptosis represents the cellular phenotype resulting from activation of genomic programs that lead to DNA damage and cell death. The objectives of this review are: a. to highlight the key evidence on apoptosis in human cardiac myocytes; b. review the key stimuli and signal transduction pathways identified in cardiac myocytes; c. discuss the significance of apoptosis in cardiac function and disease; d. suggest potential novel therapeutic strategies for cardiac diseases based on modulation of selected molecular targets in cardiomyocyte apoptosis. [ABSTRACT FROM AUTHOR]

Open heart surgery involves substantial stress for cardiac myocytes and thus the risk of cellular damage. Particularly, open heart surgery implies cardiac arrest for a quiet and bloodless surgical field. The physiological blood flow via the coronary arteries is interrupted by cross-clamping of the ascending aorta and the heart is perfused temporarily with some type of cardioplegic solution. These solutions contain non-physiologic ion concentrations to arrest electromechanic coupling. Together with hypothermia, cardioplegia results in reduction of the energy requirements of the heart by up to 97% (1,2). Nevertheless, a distinct depression of cardiac contractility is observed early in the postoperative period (3). The extent of this depression is directly related to patient survival (4). The reasons for the delayed recovery of the heart are poorly understood but cellular trauma or potentially apoptosis may be involved (5). Given this background information, a better understanding and further improvements of cardioplegic strategies are certainly needed. [ABSTRACT FROM AUTHOR]

Studies on myocardial senescence are far from being academic for several reasons, Epidemiological studies have shown that diseases of the heart are one of the major causes of mortality among overall population and the main cause of death in people after 65 years of age (1). Therefore, it is of major importance to determine the physiological structure and function of the heart in healthy aged persons and to assess the limits of normality in all age groups. The clinical problem is far from being simple because obviously the basic process of senescence is intimately associated with an increased incidence of arterial hypertension, atheroclerosis, cancer, and also with several modifications in physical activity and nutritional status which all may seriously modify the myocardial structure. It is possible to carefully select aged people who have normal blood pressure and no clinical history of coronary disease, but anatomical studies have demonstrated the high incidence of occult coronary stenosis in people who die from all causes (2). Therefore, it would be very difficult to eliminate such a disease only on the basis of clinical criteria. It is also ethically difficult to organize a large epidemiological study on aging which would include routine coronarography (reviewed in 2-5). The advent of non invasive imaging techniques such as electron-beam computed tomography (6) may prove to be of value in this setting. From a pure economical point of view, it is quite important to know whether aged myocardium behaves like myocardium of adult persons in their responses to various stimuli and drugs, and whether it would be more suitable to perform the first screening of new therapies in senescent animal models. [ABSTRACT FROM AUTHOR]

Congestive heart failure (CHF) is a final common pathway of different etiologies that results in a compensatory hypertrophy of myocytes which increase their size and the expression of contractile and other proteins normally expressed only during foetal development (1). [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that programmed cell death plays an important role in myocardial infarction. The occurrence of programmed cell death has clearly been shown in several clinical (1,2,3) and experimental settings involving myocardial injury. Experimental data in vivo and in vitro suggest that cardiomyocytes are able to undergo apoptosis during hypoxia (4,5), hypoxia-reoxygenation (6,7), myocardial infarction (8,9), ischemia-reperfusion (10,11), and heart failure (12,13). Based on these studies the present concept of myocardial injury attributes the major portion of cell loss during cardiac ischemia and reperfusion to primary necrosis (14,15). However, based on the observation that apoptosis can be the early and predominant form of cell death in infarcted human myocardium, the possibility of apoptosis as inducer of secondary necrosis has already been raised (9,16). Thus, investigating the role of programmed cell death in myocardial infarction as well as documenting its underlying mechanisms may lead to new therapeutic strategies to prevent serious cell loss following ischemia and reperfusion. [ABSTRACT FROM AUTHOR]

A better understanding and more effective treatment of acute coronary syndrome and postangioplasty restenosis remain major issues in clinical cardiology. As for acute coronary syndromes, from the pathobiologic perspective, instability of coronary atheroma (e.g. plaque rupture), and subsequent thrombosis may result in myocardial infarction and death, as well as the progression of the arteriosclerotic disease. The underlying factors and mechanisms causing plaque rupture are not completely understood. Recent investigational work on human vulnerable lesions shows a low density of smooth muscle cells (SMCs) and collagen as well as an increased frequency of inflammatory cells, associated with a considerable tissue degrading activity, to be basically implicated in the breakdown of the plaque fibrous cap (1-8). Indeed, elimination of SMCs via apoptosis (programmed cell death) may contribute to a weakened plaque texture and to a reduced production and deposition of extracellular matrix proteins, both leading to plaque instability. [ABSTRACT FROM AUTHOR]

The balance between growth and apoptosis: a key determinant of cardiovascular structure. Cardiovascular hypertrophy is an important feature of hypertension (1). However, the mechanisms regulating cardiovascular mass remain poorly defined. Spontaneously hypertensive rats (SHR) are born with elevated cardiovascular mass and DNA content, indicating the influence of genetic factors (2). Hypertrophy also develops secondarily to an increase in mechanical load as in aortic coarctation, or to chronic endocrine stimulation with, e.g., angiotensin II (AngII) (3,4). Hypertrophy which is associated with increased DNA replication is less readily reversible than hypertrophy that is solely due to increased protein synthesis without de novo DNA synthesis. Thus, in the vascular wall, DNA content (due to SMC hyperplasia or polyploidy (5)) may be considered as a record of past episodes of vascular growth, contributing to the persistence of the hypertensive disease. The prevention or regression of cardiovascular hypertrophy is now considered a key therapeutic target in the reduction of hypertension-associated morbidity and mortality. Apoptosis is an ubiquitous and highly regulated form of programmed cell death that is involved in tissue morphogenesis and homeostasis as the essential counterpart of cell replication (6,7). In this context, the balance between cell growth and apoptosis is a potential determinant of cardiac structure during development, disease and therapy (8). [ABSTRACT FROM AUTHOR]

Cell death in the cardiovascular system by apoptosis has received considerable attention in recent years. Cardiac and vascular cell death by apoptosis is not only a feature of embryologic and neonatal development, but can be elicited by a variety of diverse stimuli (Table I) and has been linked to virtually every major cardiovascular disease or disorder (Table II). In many of these disorders, particularly those leading to chronic heart failure, myocyte cell death/loss is usually accompanied by an increase in fibrous tissue content (1). Excessive fibrosis in the presence of myocyte loss has been advocated as a basis for impaired myocardial function in these disease states. The spontaneous hypertensive rat presents a clear example of the imbalance that exists as heart failure evolves (2). In this experimental model, increased cardiac myocyte apoptosis (Figure 1C) can be linked to the reduction in myocyte fractional mass (Figure 1A) as the hearts progress to failure. During this same time, there is a substantial increase in the fibrotic fractional area of the heart (Figure IB). [ABSTRACT FROM AUTHOR]

In the interstitium, the majority of cells are fibroblasts (1,2). Apoptosis or programmed cell death is an essential stage of cell cycle in cardiac morphogenesis during development and of central importance in maintaining homeostasis by eliminating the damaged and dysfunctional fibroblasts which will be replaced by new generation of cells. The mechanisms of apoptosis in cardiac fibroblasts are vastly unknown and in depth examination of various intracellular pathways responsible for apoptosis in response to environmental stress are yet to be performed. Relatively more is known on signals controlling apoptosis in cardiac myocytes than in cardiac fibroblasts. This issue is discussed in detail in separate chapter. Based on as yet limited information on both systems it is evident that the intracellular mechanisms and extracellular inducers of apoptosis in cardiac fibroblasts are not similar to those in post-mitotic cardiac myocytes. It is also evident that under environmental stress, such as hypoxia, which would cause apoptosis and cell death in cardiac myocytes, cardiac fibroblasts survive if not indefinitely, at least longer. This resilience lends support to the notion that cardiac fibroblasts may indeed have a mission to protect other cardiac cells or to compensate for their loss. In the past decade a growing body of evidence demonstrating various functions of cardiac fibroblasts has emerged and their role in the regulation of biological responses of other cardiac cells during development, normal growth, aging, ventricular hypertrophy and heart failure after myocardial infarction has been recognized. [ABSTRACT FROM AUTHOR]

Apoptosis is an active process of cell death that occurs both under physiologic and pathophysiologic conditions. Specifically, apoptosis has been involved in vasculogenesis and atherosclerosis, inflammation, as well as wound healing, respectively. Its hallmark is the cleavage of genomic DNA into nucleosomal fragments of 180 bp (1). Although it has not been established to what extent endothelial cell death occurs in vivo, there is increasing evidence that endothelium may become apoptotic in various disease states. [ABSTRACT FROM AUTHOR]

As we have seen in the previous chapters, apoptosis is an evolutionary conserved process that is ubiquitous within the living multicellular organism, essential for function and development. In this chapter we aim to introduce the concept of necrosis to highlight the unique process of apoptosis, discuss the features of apoptosis and importantly discuss the difficulties in identifying programmed cell death. [ABSTRACT FROM AUTHOR]

Apoptosis is an evolutionarily conserved form of cell suicide. Cells that die by apoptosis are disassembled in a stereotypical manner resulting in a characteristic ‘apoptotic morphology'. It was this characteristic, uniform morphology displayed by cells during apoptosis which led to the assumption that cells contain a similar execution machinery running according to a program present in all cells. The apoptosis-inducing stimuli are extremely diverse, engage sometimes totally different signalling pathways but are finally translated into the same response of a co-ordinated cell death. Furthermore, induction of apoptosis is sometimes very rapid, in the range of minutes to hours from receiving the signal until the first apoptotic signs appear. For such a fast event, time is too short to start the synthesis of new proteins executing the apoptotic program. Thus, all the components of the death machinery are present in a dormant form and are rapidly converted if necessary. In recent years many of the molecules involved in apoptotic death have been identified and functionally assigned to different stages of apoptosis. The final stage, also called execution, is initiated and co-ordinated by a recently identified class of cysteine proteases termed caspases. [ABSTRACT FROM AUTHOR]

In animal models and in patients with end-stage heart failure, a small fraction of cardiac myocytes undergoes programmed cell death (apoptosis) (1-4). In general, cardiac failure is preceded by a hypertrophic response of the myocardium, that allows the heart to maintain cardiac output despite a chronic increase in hemodynamic load. However, sustained hemodynamic overloading eventually causes a transition from hypertrophy to heart failure, characterized by chamber dilatation, progressive contractile dysfunction and impaired survival. The observation that the prevalence of apoptotic cardiomyocytes is increased in the failing heart but not during the initial stage of compensatory hypertrophy has given rise to the hypothesis that cardiac myocyte dropout by apoptosis may be one mechanism contributing to the progression of cardiac hypertrophy to heart failure (5,6). [ABSTRACT FROM AUTHOR]

The number of cells in any cellular biological system is determined by the balance of cell proliferation and cell death. Changes result in tissue growth or atrophy. The control of this equilibrium is crucial for the developing and the fully differentiated organism. Morphogenesis, gain and maintenance of organ function and response to various types of cell stress require mechanisms tightly controlling this equilibrium. The development of digits and the reorganisation and loss of thymic cells during mammalian development, the remodelling of bones in response to various forces are examples for processes depending on major shifts of this equilibrium that must be regulated extraordinarily accurate. An imbalance of cell proliferation and cell death may be the primary cause of diseases. Moreover, the seize of organs, animals and human beings eventually are determined by this balance. [ABSTRACT FROM AUTHOR]

The process of apoptosis is often subdivided into three phases: the initiation phase which depends on the apoptosis stimulus, the effector phase which underlies regulation of intracellular signaling and the degradation phase which is common to all forms of apoptosis and which is beyond regulation (1). The Bcl-2 family represents one of the most important families of apoptosis relevant proteins acting in the effector phase of apoptosis. In most cases of programmed cell death Bcl-2 proteins influence the decision of a cell to survive or to die. This review will focus on the basic molecular function of Bcl-2 family members in apoptosis as well as the interplay of some of the bcl-2 members with mitochondria in the context of mitochondrial permeability transition and mitochondrial release of apoptogenic factors. [ABSTRACT FROM AUTHOR]

The tumor suppressor gene p53 plays a major role in cellular stress response and has been found to be mutated or deleted in more than half of all human tumors. Many signal pathways and factors contribute to control the action of p53. Here we will focus on the control function of p53 after cell cycle activation by oncogenes. [ABSTRACT FROM AUTHOR]

There is an increasing body of evidence suggesting an important role of apoptosis for cardiac development and diseases. This is based on the observation that in animals and humans the ontogenesis of the normal heart is characterized by the appearance of apoptosis peaking in the perinatal period (1) and in specific regions of the heart (2). Furthermore, myocardial infarction has been shown to be associated with apoptosis in rats (3) and humans (4). Additionally, apoptosis is evident in the heart of patients suffering from certain conductance disturbances (2) as well as in human cardiomyopathies, including the arrhythmogenic right ventricular dysplesia (5) and dilated cardiomyopathy (6). Those studies are important not only because of their proof of apoptotic cell death in yet another organ, but particularly because they let us understand that the capacity for apoptotic cell death exists in both mitotic cells and in post-mitotic cells. However, only little information exists regarding the identification of stimuli responsible for the induction of apoptosis in the heart. [ABSTRACT FROM AUTHOR]

CD 137 (ILA/4-1BB) is a member of the TNF receptor family and was identified in screens for genes induced upon lymphocyte activation (1,2). CD 137 is expressed by activated lymphocytes and expression its is strictly activation dependent (3). Expression of CD137 can also be induced in non-immune cells, like chondrocytes (4). In vivo, the highest expression of CD137 has been found in blood vessel walls. Since expresssion and function of CD 137 are not yet investigated in the heart, lymphocytes serve as a model. The gene for human CD 137 resides on chromosome Ip36, and this chromosomal region is associated with mutations in several malignancies (6). [ABSTRACT FROM AUTHOR]