Infarct-related artery occlusion, tissue markers of ischaemia, and increased apoptosis in the peri-infarct viable myocardium (original) (raw)
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Circulation, 2002
Background-Myocardial apoptosis persists beyond the acute phases of acute myocardial infarction (AMI) and is associated with left ventricular (LV) remodeling. Infarct-related artery (IRA) patency is considered a favorable prognostic factor after AMI and may be associated with more favorable LV remodeling because of reduced apoptosis at the site of AMI. The aim of this study was to assess the influence of IRA status on apoptotic rate (AR) in the hearts of subjects dying late after AMI. Methods and Results-We used colocalization for in situ end-labeling of DNA fragmentation and immunohistochemistry for caspase-3 to calculate the AR at time of death (12 to 62 days after AMI) in 16 hearts with persistently occluded IRAs and in 8 hearts with patent IRAs. No significant differences were found when comparing the clinical characteristics of the 2 groups. Occluded IRA was associated with significantly higher AR at site of infarction (25.8% [interquartile range 20.9% to 28.5%] versus 2.3% [interquartile range 0.6% to 5.0%], PϽ0.001). This strong correlation between IRA occlusion and AR remained statistically significant even after correction for clinical characteristics such as sex, age, history of previous additional AMI or heart failure, transmural AMI, anterior AMI, fibrinolytic treatment, time from AMI to death, trauma as cause of death, and multivessel coronary disease (Pϭ0.003). Conclusions-A significantly higher AR was associated with persistent IRA occlusion late post-AMI. These data may suggest that the post-AMI benefits observed with a patent IRA (the "open-artery hypothesis") may in part be due to reduced myocardial apoptosis.
The FASEB Journal, 2009
In view of the conventional wisdom in the cardiology literature that apoptosis is extensive early after myocardial ischemia, predicated largely from results with the TUNEL assay known to be nonspecific, this study was performed to delineate its extent with multiple assays and at multiple intervals. Coronary occlusion with and without subsequent revascularization was induced in 10-wk-old C57BL6 mice subjected to 1 or 4 h of transient ligation followed by 24 h of reperfusion, or 24 h persistent ligation. Apoptosis was quantified throughout the left ventricle immunohistochemically by assay of TUNEL, single-stranded DNA (ssDNA), and cleaved caspase 3; electron microscopy (EM); and activity assays of caspase 3 and 8. TUNEL staining was marked, but ssDNA and cleaved caspase 3 staining were significantly less (P<0.001 compared with TUNEL), and apoptosis defined by EM was virtually absent in all groups. Caspase 3 and caspase 8 activities per milligram protein were not significantly different from those in normal hearts. Only rare, potentially apoptotic cells were seen by EM in hearts from any group. Thus, the results with TUNEL were not specific, and the extent of apoptosis was markedly less than that predicated on the results with the TUNEL procedure. Apoptosis is de minimus early after transitory or persistent ischemia, though it is overestimated by TUNEL assays. Thus, antiapoptotic interventions per se are not likely to preserve substantial amounts of myocardium early after ischemic insults.-French, C. J., Spees, J. L., Tarikuz Zaman, A. K. M., Taatjes, D. J., Sobel, B. E. The magnitude and temporal dependence of apoptosis early after myocardial ischemia with or without reperfusion. FASEB J. 23, 1177-1185 (2009) Key Words: multiple assays ⅐ infarction ⅐ TUNEL ⅐ caspase 3 ⅐ ssDNA 1177 0892-6638/09/0023-1177 © FASEB
Scholarly Research Exchange, 2009
The objective of the present review was to examine apoptosis in patients with acute myocardial infarction (MI) and to address (i) the prevalence of apoptosis in acute MI, (ii) techniques to determine apoptosis, (iii) time period from the onset of acute MI to the detection of apoptosis, (iv) criticisms about apoptosis in acute MI. A systematic literature search identified over 20 publications comprising over 400 patients. The prevalence of apoptosis varied from over 90% in nuclear imaging studies using annexin binding to 0.25% in an autopsy study using monoclonal antibody to single-stranded DNA. Apoptosis was present in 50-60% of infarcted hearts within 24 hours of MI (detected by Bax and activated caspase-3), 26% of myocytes in patients who died within 11 days of MI (pooled mean from 5 studies using only TUNEL staining), and 12% of the myocytes of patients who died, on average, 20 days after onset of MI (pooled mean from eight studies using dual staining with caspase-3 plus TUNEL). Criticisms of the TUNEL assay appear unjustified as TUNEL is at least 85% specific using caspase-3 activation as a marker of apoptosis. Taken together, DNA fragmentation on agarose gel electrophoresis, TUNEL staining of nuclei, caspase-3 activation, bcl-2 and Bax expression, and annexin V binding overwhelming support apoptotic cell death as an important component of MI. The amount of cardiac apoptosis correlates with the presence of heart failure and fatal arrhythmias. Heart failure as a complication of MI carries a high mortality and indicates the amount of myocardium lost during the infarct. Taken together, these findings suggest the need for clinical trials in acute MI to confirm whether inhibition of apoptosis can reduce patient morbidity and mortality.
Ischemia and apoptosis in an animal model of permanent infarct-related artery occlusion
International Journal of Cardiology, 2007
Apoptosis is a pathologic feature of cardiomyocytes in acute myocardial infarction (AMI) and heart failure. The temporal course of apoptosis in the peri-infarct area in the weeks following an AMI is still uncompletely defined. In order to study the time course of apoptosis after AMI, 16 rabbits underwent left coronary artery ligation and were sacrificed at 16, 26, 35, and 56 days after surgery. Increased apoptotic rate (AR) was observed at in the peri-infarct region than in remote myocardium (5.4% [2.5-9.6] vs 0.4% [0.1-0.9], respectively, P b 0.001) and than in shamoperated cases (0.01% [0-0.02], P b 0.001). A gradual decrease of AR in the peri-infarct region was observed over time with a 90% reduction at 8 weeks after coronary ligation.
The role of apoptosis in myocardial ischemia: a critical appraisal
Basic Research in Cardiology, 2001
The role of apoptosis in myocardial ischemia: a critical appraisal ˾ Abstract The role of apoptosis in cardiac ischemia is not clarified yet. Own data show that suicidal cell death is apparently not important in global ischemia where it only affects a small number of myocytes (8 %) while the majority of cells, i.e. 92 % die by oncosis. In acute regional ischemia it is most probably not a decisive factor. However, more solid data are needed to justify this statement. Human hibernating myocardium shows an activation of the apoptotic cascade, i.e., apoptosis might contribute to cell loss in this pathophysiological situation of multiple ischemic episodes. Manifold unresolved issues contribute to problems in determining the role of apoptosis in ischemia. These include 1) Uncertainty of the duration of the apoptotic cascade from activation of death receptors at the cellular membrane until DNA fragmentation occurs, 2) The role of the mitochondrial pathway, 3) The mode of removal of myocytes after cell death has occurred, 4) Technical problems such as specificity of the TUNEL method, detection of low abundance proteins such as activated caspases or cytochrome C, statistical considerations. These issues and many others should be clarified before any definite conclusion as to the role of apoptosis in ischemia may be drawn. A. Elsässer et al. 225 The role of apoptosis in myocardial ischemia: a critical appraisal í
European Journal of Heart Failure Supplements, 2003
Background: Cardiac remodelling after acute myocardial infarction (AMI) is characterised by molecular and cellular mechanisms involving both left and right ventricles, and biventricular failure identifies patients with an extremely unfavourable prognosis. Aims: To assess whether a link exists between increased myocardial apoptotic rates (AR) at sites of recent infarction and patterns of unfavourable cardiac remodelling, such as biventricular enlargement after left ventricular (LV) infarction. Methods: Twelve patients with recent AMI involving the LV and not the right ventricle (RV) and with permanent infarct related artery occlusion were selected at necropsy. Gross pathological characteristics, such as LV and RV dilatation, and AR at site of infarction were assessed. Potential false positive results (DNA synthesis and RNA splicing) were excluded from the cell count. Results: RV enlargement, defined as a tricuspidal ring greater than 120 mm, was found in five cases and was associated with LV dilatation. These patients showed significantly higher AR than the others. When the subjects were divided into three groups according to progressive cardiac remodelling (absence of cardiac dilatation, isolated LV dilatation, and biventricular enlargement), the last group had significantly higher ARs than the other two groups, showing that myocardiocyte apoptosis is increased in more unfavourable forms of cardiac remodelling. Conclusion: Patients with severely unfavourable cardiac remodelling, such as biventricular enlargement, have extremely high myocardiocyte apoptosis at necropsy, even late after LV myocardial infarction, supporting the role of myocardiocyte loss in determining post-infarction adverse remodelling.
Reduced post-infarction myocardial apoptosis in women: a clue to their different clinical course
Heart, 2005
H eart failure (HF) is less prevalent and has a better prognosis in women than in men. Also, the outlook after acute myocardial infarction (AMI) is more favourable in elderly women. 1 Such sex related differences are probably related to sex specific cardiac remodelling processes. 2 However, despite several hypothetical pathogenetic mechanisms, there are no established explanations.
Journal of Clinical Pathology, 2003
Background: Cardiac remodelling after acute myocardial infarction (AMI) is characterised by molecular and cellular mechanisms involving both left and right ventricles, and biventricular failure identifies patients with an extremely unfavourable prognosis. Aims: To assess whether a link exists between increased myocardial apoptotic rates (AR) at sites of recent infarction and patterns of unfavourable cardiac remodelling, such as biventricular enlargement after left ventricular (LV) infarction. Methods: Twelve patients with recent AMI involving the LV and not the right ventricle (RV) and with permanent infarct related artery occlusion were selected at necropsy. Gross pathological characteristics, such as LV and RV dilatation, and AR at site of infarction were assessed. Potential false positive results (DNA synthesis and RNA splicing) were excluded from the cell count. Results: RV enlargement, defined as a tricuspidal ring greater than 120 mm, was found in five cases and was associated with LV dilatation. These patients showed significantly higher AR than the others. When the subjects were divided into three groups according to progressive cardiac remodelling (absence of cardiac dilatation, isolated LV dilatation, and biventricular enlargement), the last group had significantly higher ARs than the other two groups, showing that myocardiocyte apoptosis is increased in more unfavourable forms of cardiac remodelling. Conclusion: Patients with severely unfavourable cardiac remodelling, such as biventricular enlargement, have extremely high myocardiocyte apoptosis at necropsy, even late after LV myocardial infarction, supporting the role of myocardiocyte loss in determining post-infarction adverse remodelling.
Apoptosis in experimental myocardial infarction in situ and in the perfused heart in vitro
Tissue and Cell, 1997
We report the appearance of apoptotic cells in experimental myocardial infarction (rabbit heart) in in situ and in vitro preparations. Apoptosis was recognized by intravital staining with Hoechst 33342 (Ho342), by nick-end labeling (TUNEL) and by DNA laddering. A steady rise in the relative number of apoptotic cardiomyocytes (apoptotic index) was noted in in situ preparations. Apoptosis was first noted 6 h after the onset of ischemia with its highest value occurring after 72 h. Apoptotic nuclei were absent in remote areas of the left and right ventricles. Apoptotic nuclei within the infarcted area showed diminished intensity of Ho342 fluorescence. Three days after ischemia, a border zone adjacent to the infarcted area consisting of apoptotic macrophages was recognized. A novel finding was the appearance of apoptotic cardiomyocytes in the isolated perfused ischemic heart. Occurring as early as 50 min after the onset of ischemia, a high apoptotic index was present adjacent to the ligature placed around the coronary artery. This observation provides the opportunity to selectively examine factors leading to apoptosis in the ischemic heart under controlled experimental conditions.