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• W2078454410 abstract "SPECIAL MEDICAL EDITORIALSClinical implications of apoptosis in hypertensive heart diseaseMarı́a A. Fortuño, Arantxa González, Susana Ravassa, Begoña López, and Javier Dı́ez Marı́a A. Fortuño Division of Cardiovascular Pathophysiology, Centre for Applied Medical Research, and , Arantxa González Division of Cardiovascular Pathophysiology, Centre for Applied Medical Research, and , Susana Ravassa Division of Cardiovascular Pathophysiology, Centre for Applied Medical Research, and , Begoña López Division of Cardiovascular Pathophysiology, Centre for Applied Medical Research, and , and Javier Dı́ez Division of Cardiovascular Pathophysiology, Centre for Applied Medical Research, and Department of Cardiology and Cardiovascular Surgery, University Clinic School of Medicine, University of Navarra, 31080 Pamplona, SpainPublished Online:01 May 2003https://doi.org/10.1152/ajpheart.00025.2003MoreSectionsPDF (390 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat the essential criterion in defining hypertensive heart disease is a greater than normal heart mass in the absence of a cause other than arterial hypertension. However, it is now accepted that besides left ventricular hypertrophy, alterations in diastolic and/or systolic cardiac function are frequently present in hypertensive patients, which may evolve to overt heart failure. In fact, as demonstrated in the Framingham study, arterial hypertension is the most common risk factor for congestive heart failure (94). In addition, hypertension has been shown to contribute to a large proportion of heart failure cases in population-based samples (82).Under a pathophysiological point of view, hypertension affects the myocardium at two different stages (for a review, see Ref.120). In both humans and animal models, pressure overload is characterized by a period of compensation in which left ventricular concentric hypertrophy normalizes systolic wall stress and contractile function is preserved. The period of adaptation, which may last for weeks in rodents and months to years in humans, is inexorably followed by a transition to cardiac failure. This transition is characterized by impaired survival, the onset of chamber dilatation with the failure of further concentric hypertrophic growth to normalize load, and progressive contractile dysfunction. A number of observations suggest that the transition to failure relates mainly to cardiomyocyte loss due to both apoptosis and necrosis (for a review, see Ref.37), changes in the composition of motor unit and cytoskeleton of cardiomyocytes (for a review, see Ref.146), and alterations in the metabolism of the extracellular matrix (for a review, see Ref. 148).Apoptosis is an energy-dependent process by which a specific genetic program leads to the activation of molecular cascades that cause cell death. Apoptosis is marked by the involution of the cell, eventuating in phagocytosis by neighboring cells. By deleting cells, apoptosis plays a physiological role in controlling cell mass and architecture in many tissues, including the myocardium. Because the molecular aspects of cardiac apoptosis have been reviewed extensively elsewhere in recent articles (11, 66,110), this report focuses on the pathophysiological implications of apoptotic cell death in cardiomyocytes. Thus, besides some considerations on the mechanisms of cardiomyocyte apoptosis in hypertension, its detrimental impact on cardiac function will be addressed. In addition, those noninvasive diagnostic tools currently under evaluation to detect cardiac apoptosis in humans will be underscored. Finally, the available evidence and perspectives of strategies aimed to inhibit cardiomyocyte apoptosis will be considered.EXPERIMENTAL AND CLINICAL EVIDENCEIt has been classically accepted that adult cardiomyocytes are not capable of proliferation and, thus, are resistant to developing apoptosis. Thus the existence of a balance between apoptotic cell death and cell regeneration in aging or pathological states of the heart has been denied until recently. In the past few years, observations have been made showing that cardiomyocyte apoptosis occurs in diverse conditions (Table1) and that cardiomyocyte apoptosis and proliferation are simultaneously present in several situations (for a review, see Ref. 6). Therefore, apoptosis is recognized, increasingly, as a contributing cause of cardiomyocyte loss with important pathophysiological consequences (for a review, see Ref. 11). Recent evidence demonstrates that cardiomyocyte apoptosis is abnormally stimulated in the heart of animals and humans with arterial hypertension (for a review, see Ref. 51).Table 1. Conditions in which increased apoptosis of cardiomyocytes has been describedConditionSpeciesDetection MethodReferencesExperimental conditionsIn the absence of heart failure Cardiac agingRat, mouseTUNEL, DNA laddering3, 48, 78 Injury due to ischemia and reperfusionRat, pig, mouse, rabbit.TUNEL, DNA laddering, electron microscopy, annexin V43,47, 49, 60, 99 Myocardial infarctionRatTUNEL, DNA laddering24, 77 Pressure-overload hypertrophyRatTUNEL, DNA laddering142 Cytokine induced NO productionRatMicroscopy, TUNEL, PARP73 In vitro gene transfection of p53RatDNA laddering121 Cardiac expression of TNF-αTG mouseHematoxylin-eosin staining22 TNF receptor knockout + coronary ligationMouse, TG mouseIn situ PCR ligation87 Cardiac-specific overexpression of TAK1TG mouseTUNEL156 Gsα overexpressionTG mouseTUNEL, electron microscopy56 StretchRatTUNEL, in situ ligation92 Genetic hypertensionRatTUNEL, caspase 3, annexin V40, 50, 125 Angiotensin II-induced hypertensionRatTUNEL, DNA laddering, caspase 336 Cardiac allograft rejectionTG, mouse, mouse, ratTUNEL, DNA laddering12, 42, 86, 139, 140In the presence of heart failure Coronary embolizationDogTUNEL, DNA laddering135 Coronary ligationRat, mouseTUNEL, DNA laddering, Hoechst staining, azantrichrome staining,14, 97, 102, 131 Ventricular pacingDogTUNEL, DNA laddering65, 93, 101 Pressure overload by aortic coarctationRatTUNEL, DNA laddering, electron microscopy31 Gα overexpressionTG mouseTUNEL, DNA laddering1 Overexpression of long-chain acyl-CoA synthetaseTG mouseTUNEL26 gp130 knockout + aortic coarctationTG mouseTUNEL, DNA laddering67 Pressure overload by arterial hypertensionRatTUNEL, DNA laddering98Clinical conditionsIn the absence of heart failure Postnatal morphogenesisHumanTUNEL, microscopy75, 76 Acute myocardial infarctionHumanTUNEL, DNA laddering9, 69, 115,134 Cardiac allograft rejectionHumanTUNEL, DNA laddering, annexin V107, 118, 122 Arterial hypertensionHumanTUNEL, caspase 3, electron microscopy57,150In the presence of heart failure Ischemic cardiomyopathyHumanTUNEL, In situ ligation, DNA laddering, caspase 3, cytochrome c62, 89, 108, 109, 112, 126, 133 Idiopathic dilated cardiomyopathyHumanTUNEL, In situ ligation, DNA laddering, DNase 1 levels, caspase 3, cytochromec62, 89, 108, 109, 112, 126, 133, 152 Acromegalic cardiomyopathyHumanTUNEL, in situ ligation54 Diabetes/hypertensionHumanTUNEL, in situ ligation55 Arrhytmogenic right ventricular dysplasiaHumanTUNEL, electron microscopy103, 144 MyocarditisHumanTUNEL143 Hypertrophic cardiomyopathyHumanTUNEL74NO, nitric oxide; TAK1, transforming growth factor-β-activated-kinase-1; gp, glycoprotein; TG, transgenic; PARP, poly(ADP-ribose) polymerase; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Experimental FindingsIncreased apoptosis has been demonstrated in the hypertrophied left ventricle of both spontaneously hypertensive rats (SHR) (40, 64, 98, 100) and rats with renal hypertension (96) compared with their normotensive control animals. In addition, an increased occurrence of cardiomyocyte apoptosis has been found in the heart from failing SHR compared with nonfailing SHR (64). The SHR is a genetic model of hypertension in which early hypertrophic adaptation to hypertension and subsequent transition to severe heart failure and premature death occur (106, 119). The transition from compensated hypertrophy to heart failure in SHR is accompanied by numerous structural and functional changes, including a reduction in the relative cardiomyocyte mass (32). Thus apoptosis might be a mechanism involved in cardiomyocyte loss that accompanies the transition from stable compensation to heart failure in this model.Clinical FindingsCardiomyocyte apoptosis has been shown to be abnormally stimulated in the hypertrophied heart of patients with essential hypertension, no angiographic evidence of coronary artery disease, and normal cardiac function (57, 150) (Fig.1). In addition, recent findings from our laboratory indicate that cardiomyocyte apoptosis is increased in hearts from hypertensive patients with congestive heart failure compared with hearts from hypertensive patients with normal cardiac function (A. González, B. López, S. Ravassa, R. Querejeta, J. Dı́ez, and M. A. Fortuño, unpublished data). On the other hand, moderate cardiomyocyte loss has been demonstrated in long-term systemic hypertension with no clinical evidence of heart failure (113, 114). Interestingly, we found a severe loss of cardiomocytes in failing hearts from hypertensive patients (A. González, B. López, S. Ravassa, R. Querejeta, J. Dı́ez, and M. A. Fortuño, unpublished data). Thus it seems that apoptosis-dependent cardiomyocyte loss precedes the impairment in ventricular function, and its exacerbation may contribute to development of heart failure in hypertensive patients.Fig. 1.Bars showing the cardiomyocyte apoptotic index (means + SE) in normotensive (NT) subjects and hypertensive (HT) patients before (b) and after (a) treatment with losartan (L) or amlodipine (A). TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. *P < 0.05 compared with values before treatment; **P < 0.01 compared with values in NT subjects. [Adapted from Ref. 57.]Download figureDownload PowerPoint POTENTIAL MECHANISMSCardiomyocyte apoptosis has been proposed to occur as a result of an imbalance among the factors that induce or block apoptosis (for a review, see Ref. 6). Alternatively, it is possible that apoptosis reflects some intrinsic abnormalities in those factors that act within the cardiomyocyte determining the resistance or the susceptibility of the cell to apoptosis (for a review, see Ref. 51).Role of Pressure OverloadMechanical overload secondary to aortic banding has been shown to induce cardiomyocyte apoptosis in the rat (142). Overstretching of isolated papillary muscles in vitro, which mimics an elevation of diastolic stress in vivo, resulted in an increase in cardiomyocyte apoptosis (25, 91). Interestingly, augmented superoxide formation and expression of the cell surface molecule involved in apoptotic death, Fas, were observed in this condition. The addition of the nitric oxide-releasing drug C87–3754 prevented apoptosis and superoxide anion formation (25). Therefore, the induction of superoxide seems to be a relevant factor in overstretching-induced cardiomyocyte apoptosis. On the other hand, mechanical stretch causes release of humoral factors from cardiomyocytes that may induce apoptosis in these cells (for a review, see Ref.130). Thus it is possible that the physical forces may facilitate cardiomyocyte apoptosis in conditions of pressure overload of the heart.Role of Humoral FactorsTwo types of findings suggest that besides the mechanic factor, local humoral factors may also contribute to cardiomyocyte apoptosis in arterial hypertension. First, increased apoptosis has been found not only in the hypertrophied left ventricle but also in the right ventricle of SHR (40, 50,52) and in the interventricular septum of hypertensive patients (57). Second, recent studies have shown that the ability of antihypertensive treatment to prevent apoptosis in SHR (40, 50, 52) and to regress apoptosis in hypertensive patients (57) is independent of its antihypertensive efficacy.Several arguments suggest that angiotensin II may be one of the humoral factors potentially involved in cardiomyocyte apoptosis in hypertension. First, cardiomyocyte apoptosis increases in angiotensin II-infused hypertensive Sprague-Dawley rats, and blockade of the angiotensin II type 1 (AT1) receptor with losartan prevents this effect despite the persistance of increased blood pressure (36). Second, an association has been found between enhanced cardiomyocyte apoptosis and exaggerated angiotensin-converting enzyme (ACE) activity in the left ventricle of SHR (40). Finally, chronic treatment with losartan at doses that do not normalize blood pressure is associated with reduction of cardiomyocyte apoptosis in both SHR (50) and hypertensive patients (57).In vitro studies have shown that angiotensin II binding of AT1 receptors triggers apoptosis by a mechanism involving activation of p53 protein and a subsequent decrease of the Bcl-2-to-Bax protein ratio, activation of caspase 3, stimulation of calcium-dependent DNase I, and internucleosomal DNA fragmentation (28, 78, 91, 125) (Fig. 2). Although angiotensin II has been shown to induce apoptosis in other cardiovascular cells through stimulation of the AT2receptor (for a review, see Ref. 104), recent findings suggest that it is unlikely that this receptor is a strong signal to induce cardiomyocyte apoptosis in vivo (137).Fig. 2.Proposed scheme for the potential mechanisms involved in cardiomyocyte apoptotic cell death in arterial hypertension. LV, left ventricle; AT1-r, angiotensin II (ANG II) type 1 receptor; gp, glycoprotein.Download figureDownload PowerPoint Role of Survival PathwaysThe transmembrane signal transducer glycoprotein (gp)130 has been proposed to exert a survival effect in cardiomyocytes, mediating apoptosis-supressor signals triggered by members of the interleukin-6 cytokine family, including cardiotrophin-1 and leukemia inhibitory factor (LIF) (for reviews, see Refs. 26 and72). Specific left ventricular gp130 knockout mice develop a rapid dilated cardiomyopathy with massive cardiomyocyte apoptosis in response to mechanical overload (131). Interestingly, an association of diminished expression of both gp130 and LIF proteins with increased cardiomyocyte apoptosis has been found in the heart of SHR (124). It thus can be hypothesized that inhibition of the gp130 signaling pathway in arterial hypertension decreases the survival capability of cardiomyocytes and makes them more susceptible to apoptotic factors. In support of this possibility are findings from our laboratory showing that compared with cardiomyocytes isolated from normotensive Wistar-Kyoto rats, cardiomyocytes isolated from SHR exhibit increased susceptibility to the apoptotic effects of angiotensin II (125).Several data suggest that ischemia is the main perturbation challenging the equilibrium between programmed cell survival and programmed cell death in the heart (for a review, see Ref.33). Specifically, a diminished energy availability may inhibit cell survival mechanisms and facilitate cell death. Coronary hemodynamic alterations and structural and functional alterations of intramyocardial arteries are common in hypertensive heart disease (for a review, see Ref. 53); thus ischemia may inhibit survival pathways and facilitate cardiomyocyte apoptosis in this condition (Fig. 2).POTENTIAL CONSEQUENCESDuring the past few years, there has been accumulating evidence in both human and animal models suggesting that activation of apoptosis is a consistent finding during the development of heart failure (for a review, see Ref. 81) (Table 1). Increased apoptosis may contribute to ventricular dysfunction and progression to cardiac failure through different pathways (Fig.3).Fig. 3.Proposed scheme for the potential pathways involving cardiomyocyte apoptosis in the development of heart failure associated with hypertensive heart disease.Download figureDownload PowerPoint Decrease of Contractile MassAs mentioned before, an association between cardiomyocyte apoptosis and cardiomyocyte loss has been found in the failing hearts of both SHR (62) and hypertensive patients (A. González, B. López, S. Ravassa, R. Querejeta, J. Dı́ez, and M. A. Fortuño, unpublished data). However, some difficulties emerge related to the interpretation of the data.Assuming that apoptosis takes 24 h to be completed, an apoptotic rate of 0.22%, as reported by González et al. (57) using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique (57), means that the heart should rapidly disappear. This contention does not consider that, as demonstrated recently in the human heart, cardiomyocytes may proliferate by mitotic division (10, 114) or regenerate from migrated indifferentiated stem cells (123). This does not imply that cell replication compensates for the extent of apoptotic loss in the diseases myocardium, but allows us to hypothesize that inadequate cardiomyocyte division may be a critical event in the evolution of the pathological heart to heart failure.On the other hand, at present, there is no information concerning the magnitude of cell loss required to depress cardiac contractility in the hypertrophied human heart when cell death occurs. The 30% loss of cardiomyocytes documented by Olivetti and colleagues (113) in the left ventricle of hypertensive patients did not seem to have reached a critical value for the development of severe ventricular dysfunction and failure. Studies in humans (23, 116, 147) have indicated that occlusion of a major coronary artery, resulting in acute myocardial infarction and a segmental loss of cardiomyocytes, leads to overt failure when destruction in muscle mass involves 40–50% of the cardiomyocyte population of the left ventricle. Whether cardiomyocyte apoptosis, which is diffuse in nature, has to result in loss of nearly 40–50% of the cells before ventricular failure ensues in humans remains an important unanswered question.Alteration of Contractile ApparatusImpaired myocardial contractile function may reflect not only a decrease in the number of viable, fully functional cardiomyocytes, but also a decrement in the function of viable cardiomyocytes, or a combination of these mechanisms (for a review, see Ref.29).It is well known that apoptosis is associated with activation of caspases that mediate the cleavage of vital and structural proteins. Communal et al. (30) reported recently that caspase 3 cleaved cardiac myofibrillar proteins, resulting in an impaired force-Ca2+ relationship and myofibrillar ATPase activity. In addition, induction of apoptosis in cardiomyocytes was associated with a similar cleavage of myofilaments. Because in cardiomyocytes apoptosis may not be complete, allowing the cells to persist for a prolonged period within the myocardium, the functional consequences of caspase activation should not be understimated. This possibility is especially relevant when we take into account the fact that overexpression of the active form of caspase 3 has been reported in the heart of hypertensive patients (57).Compromise of Ventricular FillingIt has been suggested that alterations of the collagen framework in the myocardium may play an important role in the genesis of diastolic dysfunction of hypertensive origin (for a review, see Ref.39). This has been supported by the finding that fibrillar collagen deposition in the cardiac interstitium of SHR (20) and hypertensive patients (41) increases left ventricular chamber stiffness and compromises left ventricular filling during diastole. The problem concerns whether this type of interstitial alteration occurs through activation of fibroblasts via humoral or mechanical factors in the absence of cardiomyocyte loss or whether cell death is required for the stimulation of the growth response of the noncardiomyocyte compartment of the myocardium. The observation of Olivetti et al. (113) that fibrosis is associated with cell loss in the hypertensive left ventricle raises questions about the mechanism responsible for the modification of the interstitium with accumulation of fibrillar collagen. As proposed by Anversa et al. (4), death of individual cardiomyocytes may be more common than generally believed, and this phenomenon may stimulate discrete healing processes contributing to the expansion of the interstitium.This proposal is further supported by the finding that failing hearts from SHR present colocalization of collagen α1-type I gene expression to areas of focal cardiomyocyte degeneration (15), suggesting that cardiomyocyte loss is associated with collagen type I production and focal scar formation in the SHR during the transition from compensated hypertrophy to failure.Left Ventricular Chamber DilationIncreasing pressure loading on the heart induces concentric ventricular hypertrophy, in which wall thickness increases without chamber enlargement. Cardiomyocyte hypertrophy is responsible for this modification in ventricular anatomy after elevation of pressure load on the heart (7). Initially, the increase in cardiomyocyte diameter normalizes the alteration in systolic wall stress generated by augmentation in afterload (61). However, when cardiomyocyte death supervenes, this balanced proportion is not maintained and loading abnormalities occur (8). This event may represent the onset of decompensation, leading to side-to-side slippage of cells, mural thinning, and chamber dilation, and depressed ventricular performance (for a review, see Ref. 5). Thus wall restructuring secondary to severe cardiomyocyte apoptosis may create an irreversible state of the myocardium, conditioning progressive dilatation, and the continous deterioration of cardiac hemodynamics with time.DIAGNOSISBecause of the detrimental effects that cardiomyocyte apoptosis may exert in hypertensive heart disease, recognizing and determining the magnitude of the phenomenon occurrence may be relevant in assessing the clinical outcome of patients with arterial hypertension. Although the most accurate detection of apoptosis is performed in situ using histopathological techniques, it requires an invasive procedure to obtain samples, and the interpretation of the results is controversial. Thus noninvasive protocols for measurement of cardiac apoptosis are being assayed.Invasive MethodsMost studies on apoptosis in human hearts have been performed in patients undergoing coronary bypass or cardiac transplantation; thus myocardial samples were obtained during surgery (62, 84, 112). In the case of hypertensive patients, transvenous endomyocardial biopsy was the procedure used to obtain myocardial samples for in situ measurement of apoptosis (57, 150). Apoptosis data obtained from tissue sections analysis offer the advantage that the cell type undergoing apoptosis is specified; however, it is obvious that besides the limitations due to the risk of complications, these invasive methods are not useful as routine procedures of diagnosis or for large-scale studies. An additional limitation is that quantification requires analysis of a large number of high-power microscopic fields, because the number of apoptotic cells may be very small, and the analysis should assume that findings observed in biopsies are representative of the whole myocardium.On the other hand, whether apoptotic cells may be recognized and quantified in situ by the currently employed techniques remains a controversial issue. The most widely technique used for apoptosis quantification in tissue sections is the TUNEL reaction (TUNEL staining or TdT labeling), based on the detection of DNA 3′ ends. However, TUNEL staining is not specific for apoptosis. In fact, using the electron microscopic TUNEL method, it has been shown that positive TUNEL staining is associated not only with apoptotic cardiomyocytes, but also with oncotic (necrotic) cardiomyocytes or even viable cardiomyocytes undergoing DNA repair (83, 111). Therefore, because the rate of apoptosis is generally very low in normal hearts as well as in diseased hearts, a high false positive rate severely limits the interpretation of TUNEL-positive cells.This problem was partially avoided by the development of theTaq and Pfu labeling techniques (34,35). Taq polymerase-generated probes identify single-base 3′ overhangs in fragmented DNA caused by endonucleases typical of apoptosis, which are not present in the blunt DNA ends resulting from exonuclease activity in necrotic cell death. The latter are labeled by Pfu polymerase-generated probes. With the use of this approach, Guerra et al. (62) reported that cardiomyocyte apoptosis occurs in end-stage cardiac failure at rates 10- to 5-fold lower than those previously reported using the TUNEL method. Nevertheless, as emphasized by Saraste and Pulkki (132), detection of DNA 3′ ends should be always accompanied by other confirmation protocols based on different apoptotic features such as caspase activation, nuclear morphological modifications, extracellular cell surface exposure of phophatidylserine, or the internucleosomal pattern of DNA fragmentation.Noninvasive MethodsBesides the ethical and technical limitations listed above, the use of cardiac biopsy samples makes it very difficult to obtain information about the extent, distribution, or time frame of apoptotic cell death. The need for new methods to gain more understanding of the dynamic pathophysiology of cardiac apoptosis has driven to the development of imaging methodologies for in vivo apoptosis monitorization and quantification.A pivotal part of the apoptoptic concept is the timely removal of the dying cell from the tissue before it causes inflammatory responses by the leakage of intracellular constituents into the surroundings. Clearance of the dying cell occurs through phagocytes, which recognize the death phenotype. Apoptosis activates mechanisms that cause the translocation of phosphatidylserine from the internal to the external leaflet of the plasma membrane (46, 145, 147). Annexin V is a phospholipid-binding protein that, in the presence of Ca2+, specifically and reversibly interacts with the phosphoserine head group of phosphatidylserine in the apoptotic cell (138).This property has been the driving force for the research of annexin V conjugated with a detectable marker such as biotin, a fluorochrome, or a radioligand as a probe to measure apoptosis in vitro (Fig.4) and in vivo in animals and patients (for a review, see Ref. 128). Hence, intra-arterial injection of fluorescently labeled annexin V has been used to study the dynamics of cardiac apoptosis in experimental cardiac ischemia, analyzing ex vivo specimens (43) and beating hearts (44). In patients with acute myocardial infarction, apoptosis of cardiac cells has been monitored after intravenous injection of technetium 99m-labeled annexin V, obtaining early and late single-photon emission-computed tomographic images (69). A similar protocol has been employed to detect cardiac allograft rejection (107) and for localizing an intracardiac tumor (68). The use of these procedures to visualize cardiac apoptosis in hypertensive patients remains to be assayed.Fig. 4.Detection of cardiomyocyte apoptosis. Cardiomyocyte nuclei were stained with 4′,6-diamino-2-phenylindole (A, arrows and arrowheads). TUNEL-positive cardiomyocyte nuclei were visualized with fluorescein isothiocyanate-conjugated extravidin (B, arrows). Annexin V-positive cardiomyocytes were stained with tetramethylrhodamine-conjugated extravidin (C, arrows).Download figureDownload PowerPoint Besides imaging studies, annexin V may be also useful for the biochemical monitoring of the apoptotic process. In this respect, it has been reported in humans that plasma levels of annexin V determined by means of ELISA are increased eightfold in the early phase of acute myocardial infarction and immediately decrease after the onset of the pain (80). Other circulating markers of apoptosis are currently under investigation. For instance, it has been recently reported that, during apoptosis, cytochromec not only translocates into the cytosol, but is secreted to the extracellular medium (127). Furthermore, patients with hematological malignances exhibit elevated serum levels of cytochromec (127). Because the release of cytochromec from mitochondria has been shown to occur during apoptosis in human heart failure (74), its potential role as a serum marker of cardiac apoptosis in chronic cardiomyopathies, including hypertensive heart disease, remains to be investigated.NMR spectroscopy and imaging have emerged as powerful noninvasive tools for clinical diagnosis and therapeutic followup. Some biochemical changes characteristic of apoptosis have been proposed as potential markers to be used in NMR techniques (136), and preliminary in vitro observations indicate that proton NMR may be useful in detecting apoptotic cell death in vivo (13,18). Current application of this protocols in patients is restricted to monitorization of cancer treatment (17), although its use to cardiac diseases has been proposed (16).TREATMENTIt has been postulated that the inhibition of cardiomyocyte apoptosis could prevent or slow cardiac failure progression, thus opening new strategies in the treatment of cardiac diseases (105). Cardiomyocyte apoptosis may be inhibited by suppressing the local factors that trigger the process, by directly blunting the intracellular apoptotic pathways, or by inducing the survival pathways (51).Antihypertensive DrugsThe in vivo effects of antihypertensive drugs on cardiac apoptosis in SHR are presented in Table2. Most reported data indicate that chronic interference of the renin-angiotensin system with either an ACE inhibitor (i.e., quinapril, enalapril, or fosinopril) or an AT1 receptor blocker (i.e., losartan) are effective in preventing cardiomyocyte apoptosis in this model (40, 50,98, 100, 154). Tea et al. (141) recently reported" @default.
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• W2078454410 title "Clinical implications of apoptosis in hypertensive heart disease" @default.
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