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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since mammalian cardiac myocytes essentially rely on aerobic energy metabolism, it has been assumed that cardiocytes die in a catastrophic breakdown of cellular homeostasis (i.e. necrosis), if oxygen supply remains below a critical limit. Recent observations, however, indicate that a process of gene-directed cellular suicide (i.e. apoptosis) is activated in terminally differentiated cardiocytes of the adult mammalian heart by ischemia and reperfusion, and by cardiac overload as well. Apoptosis or programmed cell death is an actively regulated process of cellular self destruction, which requires energy and de novo gene expression, and which is directed by an inborn genetic program. The final result of this program is the fragmentation of nuclear DNA into typical 'nucleosomal ladders', while the functional integrity of the cell membrane and of other cellular organelles is still maintained. The critical step in this regulated apoptotic DNA fragmentation is the proteolytic inactivation of poly-[ADP-ribose]-polymerase (PARP) by a group of cysteine proteases with some structural homologies to interleukin-1 beta-converting enzyme (ICE-related proteases [IRPs] such as apopain, yama and others). PARP catalyzes the ADP-ribosylation of nuclear proteins at the sites of spontaneous DNA strand breaks and thereby facilitates the repair of this DNA damage. IRP-mediated destruction of PARP, the 'supervisor of the genome', can be induced by activation of membrane receptors (e.g. FAS or APOI) and other signals, and is inhibited by activation of 'anti-death genes' (e.g. bcl-2). Overload-triggered myocyte apoptosis appears to contribute to the transition to cardiac failure, which can be prevented by therapeutic hemodynamic unloading. In myocardial ischemia, the activation of the apoptotic program in cardiocytes does not exclude their final destiny to catastrophic necrosis with release of cytosolic enzymes, but might be considered as an adaptive process in hypoperfused ventricular zones, sacrificing some jeopardized myocytes to regulated apoptosis, which may be less arrhythmogenic than necrosis with the primary disturbance of membrane function.
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PMID:Apoptosis in the heart: when and why? 897 66

Various alterations in molecular and cellular events have been considered as possibly contributing to the cardiac remodelling that occurs during the transition from compensated hypertrophy to heart failure. The aim of the present study is to clarify (1) whether cardiac apoptosis occurs during the transition from compensated hypertrophy to decompensated heart failure, and (2) whether expression of the genes encoding Bax (an apoptosis inducer) and Bcl-xL and Bcl-2 (apoptosis inhibitors) is altered during this transition. We used 12-month-old and 20-month-old male spontaneously hypertensive rats (SHR(12) and SHR(20) respectively) and age-matched Wistar-Kyoto rats (WKY(12) and WKY(20) respectively). These rats were killed after measurement of haemodynamic parameters by transthoracic echocardiography and use of a tipmanometer via the right carotid artery. The expression of bcl-2, bcl-xL and bax was analysed by Northern blotting. Samples were also fixed in 4% paraformaldehyde for in situ nick end-labelling (TUNEL) methods and immunohistochemistry. SHR(12) had well compensated left ventricular hypertrophy with normal fractional shortening and normal end-systolic wall stress. In contrast, the hearts of SHR(20) developed decompensated dilatation, with a decrease in fractional shortening and an increase in end-systolic wall stress. TUNEL-positive cells were seen exclusively in the hearts of SHR(20). The major cell types that showed TUNEL-positive nuclei were non-cardiomyocytes. The expression of bax remained unchanged during the transition to heart failure. However, there was increased expression of bcl-xL in the failing stage, whereas the expression of bcl-2 remained unchanged. Immunohistochemical studies revealed that Bcl-xL protein was up-regulated in the hearts of SHR(20). In conclusion, non-cardiomyocyte apoptosis may play a contributory role in the remodelling that occurs in the transition from compensatory hypertrophy to decompensated heart failure. In addition, it is suggested that enhanced expression of bcl-xL plays an important role in the preservation of cardiomyocytes during this transition.
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PMID:Contribution of non-cardiomyocyte apoptosis to cardiac remodelling that occurs in the transition from compensated hypertrophy to heart failure in spontaneously hypertensive rats. 1040 80

An autopsy case of a malignant pericardial mesothelioma in a 27-year-old man with no history of exposure to asbestos is reported. He was admitted for heart failure due to pericardial effusion of unknown origin and surgically drained, but later died. The diagnosis of a malignant pericardial mesothelioma was made on the basis of histologic, immunohistochemical and ultrastructural findings. The tumor was located on the pericardium, but autopsy revealed that it had spread extensively in the mediastinum and the lungs. Microscopically, the tumor cells were epithelial like and contained histochemically demonstrable glycogen and hyaluronic acid. Immunohistochemical studies of the tumor demonstrated positive immunoreactivity for cytokeratin 19, muscle actin HHF35, epithelial membrane antigen, CA125, p53 and p21WAF1/CIP1 whereas the tumor was negative for cytokeratins 10 and 17, carcinoembryonic antigen, vimentin, epithelial antigen BerEP4, S-100, c-erbB2 and bcl-2. A high MIB-1 labeling index was noted. Under the electron microscope the tumor cells exhibited long, thin villi. The operation and autopsy findings thus revealed this to be a very rare case of malignant pericardial mesothelioma in a young man.
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PMID:An autopsy case of a malignant pericardial mesothelioma in a Japanese young man. 1050 29

Apoptosis and proliferation of myocytes were studied in human heart failure (HF). Endomyocardial samples from the right ventricle of 38 patients with terminal HF were compared with 10 traffic accident victims without a history of cardiovascular disease. The TUNEL method was used for the detection of apoptosis, and immunohistochemical methods were used for the evaluation of p53, bcl-2, proliferation cell nuclear antigen (PCNA), and proliferation marker MIB-1. Apoptosis of cardiomyocytes, which was not p53-dependent, was present in 0.07 % of myocytes in HF, whereas no apoptotic myocytes were found in the control group (p < 0.01). An increased expression of bcl-2 was found in HF compared to controls (p < 0.01), yet bcl-2 failed to protect myocytes from apoptosis. Increased expression of proliferation markers was found in myocytes in HF compared to controls (PCNA labeling: 3.7% vs. 1.2%, p < 0.01; MIB-1 labeling: 0.1% vs. 0%, p< 0.01). Nevertheless, no mitotic figures in cardiomyocytes were found in our specimens. The volume density of interstitium was 22% in HF vs. 10% in the control group (p < 0.01). In conclusion, apoptosis of cardiomyocytes and fibrosis play an important role in HF, whereas clinical importance and the rate of myocyte proliferation remain to be determined.
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PMID:Apoptosis and proliferation of cardiomyocytes in heart failure of different etiologies. 1098 14

Whether alcohol-induced heart failure is caused by a direct toxic effect of ethanol, metabolites, or whether it is a secondary result of neurohumoral, hormonal, or nutritional factors is not clear. To address this question a Langendorff retrograde coronary perfusion model of rat heart was used to study the effect of 0.5% (v/v) ethanol (n = 7) and 0.5 mM acetaldehyde (n = 9) on left ventricular expression of ANP, BNP, p53, p21, TNF-alpha,bax, bcl-2 as well as on DNA-fragmentation. Ethanol infusion of 150 min duration significantly induced both ANP and p21 mRNA expression of ventricular myocardium compared with hearts infused with vehicle (n = 8). Acetaldehyde did not exert any significant effects on any of the parameters studied, although the mean expression of TNF-alpha tended to be lower in the acetaldehyde-treated hearts than in control hearts. No evidence of increased DNA-fragmentation was found in ethanol or acetaldehyde treated groups. We conclude that ethanol per se is capable of inducing genes associated with hypertrophy and impaired function of the heart whereas a significant apoptosis is not involved in the initial phase of alcohol-induced cardiac injury.
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PMID:Ethanol infusion increases ANP and p21 gene expression in isolated perfused rat heart. 1118 Oct 50

Heart-specific inhibition of survival pathway gp130 was recently shown to sensitize transgenic mice towards stress stimuli, resulting in rapid onset of cardiac dilatation and heart failure. In order to identify further survival pathways we evaluated the role of transcription factor nuclear factor-kappa B (NF-kappa B) in tumour necrosis factor-alpha (TNF-alpha)-induced apoptosis of cardiomyocytes. TNF-alpha stimulation (10 ng/ml) of both H9c2 cells and primary cardiomyocytes isolated from neonatal Wistar rats resulted in rapid nuclear translocation of NF-kappa B complexes. The NF-kappa B complexes consisted of rel-proteins p50 and p65, as revealed by supershift analysis. Addition of proteasome inhibitor MG132 or adenoviral expression of a truncated I kappa B alpha (I kappa B Delta N) inhibited TNF-alpha-induced NF-kappa B nuclear translocation in a dose-dependent manner. Both neonatal cardiomyocytes and H9c2 cells were resistant to TNF-induced apoptosis. However, specific inhibition of NF-kappa B activation by Ad5-I kappa B alpha Delta N (MOI=50) or MG132 (5 microm) increased apoptosis as measured by subG1-assay (H9c2 cells) and annexin V binding/propidium iodide (neonatal cardiomyocytes, FACS-analysis: 7+/-2% to 26+/-5% annexin V positive/PI negative), respectively. TUNEL-assay double-stained with anti-alpha-sarcomeric actin confirmed apoptosis of neonatal cardiomyocytes. Furthermore, caspase-3 activation was increased by 52+/-7% in neonatal cardiomyocytes after TNF alpha+Ad5-I kappa B alpha Delta N compared to TNF alpha+Ad5-control treatment. Protein levels of hiAP1, hiAP2, x-iAP, bcl-2 and bcl-x(L) were neither downregulated by NF-kappa B inhibition nor upregulated by TNF-alpha stimulation. In summary, cardiomyocytes utilize transcription factor NF-kappa B to activate survival factors in the context of TNF-alpha stimulation. As locally increased levels of TNF-alpha have been detected in heart failure, NF-kappa B activity is essential for cellular homeostasis in the heart.
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PMID:Effect of NF-kappa B Inhibition on TNF-alpha-induced apoptosis and downstream pathways in cardiomyocytes. 1144 25

The aim of this study was to test the hypothesis that persistent myocardial apoptosis contributes to progression of heart failure in a canine model of pacing-induced cardiomyopathy. Dogs were paced at 250 beats per minute for 1 week (n=9), 3 weeks (n=14) and 4 weeks (n=14) with normal dogs served as controls (n=12). Myocardial apoptosis was assessed by multiple methods including DNA fragmentation and in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, bax and bcl-2 protein expression, and caspase activity. Pacing produced a progressive increase in left ventricular (LV) end diastolic pressure (LVEDP) and plasma norepinephrine levels with no significant increase in LV mass. The number of apoptotic cells was markedly increased after 1 week of pacing and remained increased at 4 weeks of pacing with characteristic DNA laddering. The increase in apoptosis was associated with bax protein expression and caspase activation while there was no detectable changes in bcl-2 protein expression. The estimated total number of apoptotic cells correlated with cardiac output and LVEDP (r=-0.69 and 0.59, respectively, P<0.001). Plasma norepinephrine and bax protein expression correlated significantly with the estimated total number of apoptotic myocytes (r=0.62 and 0.42, respectively, P<0.01). In conclusion, an early and persistent activation of myocardial apoptosis and pro-apoptotic factors is likely an important mechanism that contributes to the progression of heart failure in canine pacing-induced cardiomyopathy.
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PMID:Early and persistent activation of myocardial apoptosis, bax and caspases: insights into mechanisms of progression of heart failure. 1203 50

Left ventricular (LV) remodeling and heart failure (HF) complicate acute myocardial infarction (AMI) even weeks to months after the initial insult. Apoptosis may represent an important pathophysiologic mechanism causing progressive myocardiocyte loss and LV dilatation even late after AMI. This review will discuss the role of apoptosis according to findings in animal experimental data and observational studies in humans in order to assess clinical relevance, determinants, and mechanisms of myocardial apoptosis and potential therapeutic implications. More complete definition of the impact of myocardiocyte loss on prognosis and of the mechanisms involved may lead to improved understanding of cardiac remodeling and possibly improved patients' care. Mitochondrial damage and bcl-2 to bax balance play a central role in ischemia-dependent apoptosis while angiotensin II and beta(1)-adrenergic-stimulation may be major causes of receptor-mediated apoptosis. Benefits due to treatment with ACE-inhibitors and beta-blockers appear to be in part due to reduced myocardial apoptosis. Moreover, infarct-related artery patency late after AMI may be a major determinant of myocardial apoptosis and clinical benefits deriving from an open artery late post AMI (the "open artery hypothesis") may be, at least in part, due to reduced myocardiocyte loss.
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PMID:Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodeling. 1238 91

In general, myocyte death in myocardial infarctions (MI) is attributed to necrosis, but recently the involvement of apoptosis has been suggested. Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. The expression of two proto-oncogenes influence apoptosis. Myocytes with positive bcl-2 immunoreactivity were seen in the heart of acute MI, localized only in the salvaged areas surrounding the infarcted tissues. Myocytes with overexpressed positive Bax immunoreactivity were observed in the salvaged areas of old MI.
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PMID:[Expression of bcl-2 and Bax protein in the failing human heart--an inhibitor or accelerator of apoptosis?]. 1253 23

One of the hallmarks of cardiomyopathy and heart failure is pronounced and progressive cardiomyocyte death. Understanding the mechanisms involved in cardiomyocyte cell death is a topic of great interest for treatment of cardiac disease. Mice null for desmin, the muscle-specific member of the intermediate filament gene family, develop cardiomyopathy characterized by extensive cardiomyocyte death, fibrosis, calcification, and eventual heart failure. The earliest ultrastructural defects are observed in mitochondria. In the present study, we have demonstrated that these mitochondrial abnormalities are the primary cause of the observed cardiomyopathy and that these defects can be ameliorated by overexpression of bcl-2 in desmin null heart. Overexpression of bcl-2 in the desmin null heart results in correction of mitochondrial defects, reduced occurrence of fibrotic lesions in the myocardium, prevention of cardiac hypertrophy, restoration of cardiomyocyte ultrastructure, and significant improvement of cardiac function. Furthermore, we have found that loss of desmin also diminishes the capacity of mitochondria to resist exposure to calcium, a defect that can be partially restored by bcl-2 overexpression. These results point to a unique function for desmin in protection of mitochondria from calcium exposure that can be partially rescued by overexpression of bcl-2. We show that bcl-2 cardiac overexpression has provided significant improvement of an inherited form of cardiomyopathy, revealing the potential for bcl-2, and perhaps other genes in the family, as therapeutic agents for heart disease of many types, including inherited forms.
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PMID:Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. 1471 96


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