Cardiomyocyte apoptosis and progression of heart failure to transplantation

Saraste, Antti; Pulkki, Kari; Kallajoki, Markku; Heikkilä, Päivi; Laine, Petri; Mattila, S; Nieminen, Markku S.; Parvinen, Martti; Voipio‐Pulkki, Liisa‐Maria

doi:10.1046/j.1365-2362.1999.00481.x

Cited by 193 publications

(145 citation statements)

References 19 publications

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“…The difference in the proportions of cardiomyocyte apoptosis have been reported in the previous studies, 10,[29][30][31] and the difference between the studies might have been due to differences in the tissue samples taken or the method used for analysis of myocardial tissue. 7,32 However, a previous literature by van Empel et al reviewed a prevalence of cardiomyocyte apoptosis ranging from 0.12 to 0.70% in myocardial biopsy specimens obtained from patients with NYHA classes III-IV heart failure, 30,[33][34][35][36][37][38][39][40] which was similar to the figure obtained in the present study. Therefore, the variation in the prevalence of cardiomyocyte apoptosis between the reported studies may not have been due to differences in the myocardial tissue samples used for analysis.…”

Section: Discussionsupporting

confidence: 90%

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction

et al. 2006

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To clarify the role of myocardial apoptosis associated with the expression of proinflammatory cytokines in human myocardial infarction (MI), we have analyzed the expression of apoptosis positive for single-stranded DNA (ss-DNA) antibody, tumor necrosis factor (TNF)-a, and interleukin (IL)-8 in 147 samples of infarcted myocardial tissue from 65 patients. ss-DNA-positive apoptotic nuclei were found mainly in cardiomyocytes in the border zones and granulation tissue cells in the infarct foci. The ss-DNA index (SI) of cardiomyocytes (average 0.13%) peaked at stage II (established myocardial necrosis), the value being significantly higher than at stages III (macrophage infiltration), IV (granulation formation), and V (scar formation) (Po0.05), whereas the SI of granulation tissue (average 0.08%) at stages III, IV, and V showed no significant differences between the three stages. These results suggest that cardiomyocyte apoptosis in the border zone is responsible for cellular loss in the acute stage of MI, whereas granulation tissue apoptosis may not be involved in the process of ventricular remodeling. TNF-a was expressed in cardiomyocytes in the border zones of infarct foci, but no significant positive correlation was found between SI and TNF-a index in cardiomyocytes (r ¼ 0.08, P ¼ 0.37), suggesting that TNF-a does not serve as a direct trigger of cardiomyocyte apoptosis in vivo. The number of IL-8-positive cells peaked at stage II, and IL-8-myeloperoxidase-double-positive neutrophils were frequently detected, indicating that infiltrating neutrophils are the predominant source of IL-8 in the infarcted myocardium. These results suggest that, in human MI, TNF-a produced by cardiomyocytes does not play a critical role in their apoptosis, and that IL-8 produced by neutrophils is responsible for the subsequent accumulation and activation of neutrophils, thus increasing the degree of myocardial damage.

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Section: Discussionsupporting

confidence: 90%

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction

et al. 2006

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“…␣1-antichymotrypsin, a serine protease inhibitor, has been reported to attenuate myocardial ischemic injury (21,22). Consistent with observations of increased apoptosis in F human hearts (19), decreased expression of ␣1-antichymotrypsin (3), metallothionein, and metallothionein 1L, may indicate that the anti-apoptosis pathway is inhibited in F hearts.…”

Section: Development and Implication Of Statistical Protocols And A Cmentioning

confidence: 53%

The gene expression fingerprint of human heart failure

Tan

Moravec

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

244

196

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Multiple pathways are responsible for transducing mechanical and hormonal stimuli into changes in gene expression during heart failure. In this study our goals were (i) to develop a sound statistical method to establish a comprehensive cutoff point for identification of differentially expressed genes, (ii) to identify a gene expression fingerprint for heart failure, (iii) to attempt to distinguish different etiologies of heart failure by their gene expression fingerprint, and (iv) to identify gene clusters that show coordinated up-or downregulation in human heart failure. We used oligonucleotide microarrays to profile seven nonfailing (NF) and eight failing (F) human hearts with a diagnosis of end-stage dilated cardiomyopathy. Biological and experimental variability of the hybridization data were analyzed, and then a statistical analysis procedure was developed, including Student's t test after log-transformation and Wilcoxon Mann-Whitney test. A comprehensive cutoff point composed of fold change, average difference, and absolute call was then established and validated by TaqMan PCR. Of 6,606 genes on the GeneChip, 103 genes in 10 functional groups were differentially expressed between F and NF hearts. A dendrogram identified a gene expression fingerprint of F and NF hearts and also distinguished two F hearts with distinct etiologies (familial and alcoholic cardiomyopathy, respectively) with different expression patterns. K means clustering also revealed two potentially novel pathways associated with up-regulation of atrial natriuretic factor and brain natriuretic peptide and with increased expression of extracellular matrix proteins. Gene expression fingerprints may be useful indicators of heart failure etiologies.

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“…In one study, terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) staining of heart tissue from 21 transplant patients with DCM revealed 0.119% TUNEL positive cardiomyocytes, indicative of apoptosis. While low, this amount was higher than in patients with ischemic heart disease (0.075%) and in control patients (<0.002%), and the amount of cardiomyocytes apoptosis positively correlated with disease progression [23].…”

Section: Evidence For Cardiomyocyte Apoptosis In Dox-induced Dcmmentioning

confidence: 64%

“…Hence, increased protection against MOMP after DOX exposure, and hence a counter-priming, is indicated by elevation of the anti-apoptotic protein BCL2 [23], by an increase of BCL2/BAX protein ratio [57] and elevation of the anti-apoptotic gene ARC in rat hearts [58,59]. As most of these studies were performed in whole hearts, further studies will reveal to what extent DOX primes or anti-primes cardiomyocytes to further pre-or post-MOMP apoptosis or to apoptosis susceptibility to cell death ligands.…”

Section: Does Dox Exposure Change Apoptosis Likelihood To Later Somatmentioning

confidence: 99%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

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Cardiomyocyte apoptosis and progression of heart failure to transplantation

Cited by 193 publications

References 19 publications

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction

The gene expression fingerprint of human heart failure

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

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