Search

Apoptosis of endothelial cells (ECs) has been suggested to play a role in atherosclerosis. We studied the synergism of hypercholesterolemia with Chlamydia pneumoniae and influenza virus infections on EC morphology and intimal changes in a minipig model. The coronary artery was excised at euthanasia (19 weeks of age) and serial sections were processed for the detection of EC apoptosis, histology, and transmission electron microscopy (TEM) studies. There was a significantly higher number of TUNEL-positive ECs in infected compared to noninfected groups [0.2942 % (interquartile ranges (IR), 0.2941; n = 26) versus 0 % (IR, 0; n = 12), p < 0.01]. Caspase-3 staining was negative. Cholesterol diet together with infections induced widening of the subendothelial space and appearance of increased numbers of foam cells. TEM revealed degenerative changes in cytoplasmic organelles and signs of EC necrosis. In conclusion, infection leads to an increase in coronary EC death and seems to exacerbate cholesterol-induced intimal thickening and foam cell accumulation.

Background: Retrograde delivery is associated with inadequate perfusion of cardioplegia to all regions of the heart, but the effects on cardiomyocyte death and functional outcome remain unknown. We compared antegrade and retrograde cardioplegia in a randomized clinical trial to see whether it has effect on cardiomyocyte apoptosis and left ventricular function., Methods: Patients underwent elective aortic valve replacement surgery due to aortic valve stenosis. They were randomly allocated to receive antegrade (n = 10) or retrograde (n = 10) cardioplegia. Apoptotic cardiomyocytes (terminal transferase-mediated dUTP nick end labeling, caspase activation) and RNA levels of apoptosis-regulating proteins were studied in transmyocardial biopsies obtained before and after the operation. Magnetic resonance imaging and transesophageal echocardiography were performed, and cardiac enzymes were measured., Results: Clinical outcome and cardiac enzyme release were comparable between the groups. Cardiomyocyte apoptosis was significantly increased (terminal transferase-mediated dUTP nick end labeling) in the left ventricle after the operation in the retrograde, but not in the antegrade group (respectively, 0.00% [0.039%] versus 0.092% [0.205%], p = 0.01; and 0.00% [0.00%] versus 0.023% [0.054%], p = 0.14). Expression of apoptosis-regulating proteins BAX, BAD, and BCL-2 were comparable between groups. By transesophageal echocardiography, the systolic mitral annulus movement was decreased immediately after the operation in the retrograde group. By magnetic resonance imaging, the left ventricle mass index was reduced preoperatively to 9 months postoperatively in the antegrade group., Conclusions: In contrast to antegrade cardioplegia, retrograde cardioplegia is associated with increased cardiomyocyte apoptosis, impaired immediate postoperative systolic function, and lack of long-term favorable left ventricle remodeling after aortic valve replacement, suggesting inadequate myocardial protection., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

High levels of antibodies (Abs) against the C-terminal end of the Trypanosoma cruzi ribosomal P2β protein, defined by the R13 peptide, are detected in sera from patients with chronic Chagas heart disease (cChHD). These Abs can cross-react with the β1-adrenergic receptor (β1-AR), inducing a functional response in cardiomyocytes. In this study, we report that a monoclonal Ab against the R13 peptide, called mAb 17.2, and its single-chain Fv fragment (scFv), C5, caused apoptosis of murine adult cardiac HL-1 cells, and this effect was inhibited by pre-incubation with the β-blocker, propranolol. In addition, apoptosis induced by mAb 17.2 might involve the mitochondrial pathway evidenced by an increase in pro-apoptotic molecule, Bax/anti-apoptotic molecule, Bcl(XL), mRNA levels. HL-1 cells also underwent apoptosis after incubation with nine of 23 IgGs from cChHD patients (39.1%) that presented reactivity against R13 peptide and β1-AR. The apoptotic effect caused by these IgGs was partially abolished by pre-incubation with R13 peptide or propranolol, suggesting the involvement of the C-terminal end of ribosomal P proteins and the β-adrenergic pathway. Moreover, we observed high rates of cardiomyocyte apoptosis in two tissue samples from cChHD patients by using a TUNEL assay and staining of active caspase-3. Our data demonstrate that Abs developed during T. cruzi infection have a strong cardiomyocyte apoptosis inducing ability, which could contribute to the heart disease developed in patients with cChHD., (Copyright © 2011 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Cardiomyocyte apoptosis might contribute to left ventricular (LV) dysfunction following cardiac surgery. Magnetic resonance imaging is considered the most accurate method of determining LV function. We compared apoptosis (by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, TUNEL, staining and detection of caspase 3 activation) and LV function after regional ischemia-reperfusion (I-R) and global cardioplegic ischemia., Methods: Pigs were randomized to undergo regional myocardial I-R for 20 + 20 min, global myocardial ischemia with cardiopulmonary bypass (CPB) for 40 min or CPB without ischemia (control), followed by 274 min of reperfusion., Results: Compared with the control group, the number of TUNEL-positive cardiomyocytes was higher in the global ischemia group with CPB (0.024 ± 0.014%; p = 0.02) and further increased in areas of unprotected regional I-R (0.444 ± 0.562%; p = 0.003, vs. control). Myocytes with active caspase 3 were detected after global and regional ischemia. The global ejection fraction did not differ between CPB and regional I-R groups., Conclusions: The use of cardioplegia and CPB efficiently protects the heart from global I-R-induced cardiomyocyte apoptosis during open heart surgery., (Copyright © 2010 S. Karger AG, Basel.)

Background: Autoantibodies against various endogenous proteins are found in myocarditis. Troponin autoantibodies are detected in patients with chronic dilated cardiomyopathy, but their presence in myocarditis remains unknown. We set out to study the presence of troponin autoantibodies in experimental viral myocarditis., Materials and Methods: BALB/c mice infected with coxsackievirus B3 Nancy strain were followed-up at days 1-7 and 2, 4, 8 and 12 weeks after infection. Levels of circulating cardiac troponin I and circulating troponin autoantibodies were measured. Transthoracic echocardiography was performed. Myocarditis was histopathologically graded and cardiomyocyte apoptosis was quantified (TUNEL)., Results: Histopathologically relatively mild acute myocarditis followed by persistent cardiomyocyte damage was observed. Rate of cardiomyocyte apoptosis was the highest on day 5 (0.16 +/- 0.01% vs. 0.03 +/- 0.01% in controls, P < 0.001). Circulating troponin I levels were increased to day 5 (45.2 +/- 6.5 ng mL(-1), P < 0.005 vs. controls). Troponin autoantibodies were detected from 2 weeks after infection (20% of animals had autoantibodies at 2 weeks, 60% at 4 and 8 weeks and 20% at 12 weeks, P < 0.05 vs. controls). Fractional shortening remained decreased after acute myocarditis (0.36 +/- 0.02 at 4 weeks, 0.30 +/- 0.02 at 8 and 12 weeks vs. 0.41 +/- 0.01 before infection, P < 0.01) parallel to development of troponin autoantibodies., Conclusion: Troponin autoantibodies are formed in experimental virus induced myocarditis following troponin I release and cardiomyocyte apoptosis. The definite role of these autoantibodies remains to be further characterized.

Objective: Apoptosis has been considered as one of the mechanisms of cardiomyocyte loss during open heart surgery. Adenosine is cardioprotective against ischemia-reperfusion injury in experimental models. The aim of this study was to find out whether the administration of single dose adenosine added to blood cardioplegia is effective in decreasing the apoptosis process., Methods: In a double-blinded randomized control intervention study, 40 patients were enrolled for elective coronary artery bypass grafting. In the adenosine group (n=20) patients received 250 microg/kg adenosine in the aortic root after cross-clamping followed by cold blood cardioplegia. In the control group (n=20) patients had only antegrade cardioplegia. Left ventricular tissue samples (from apex) were taken before and after the bypass. The apoptotic cells were identified by dUTP nick-end labeling (TUNEL) using an apoptosis detection kit. The number of TUNEL-positive cardiomyocytes was expressed as percentage of the total number of cardiomyocytes in histological tissue sections., Results: The groups were closely identical in demographic data, cross-clamp time, cardiopulmonary bypass time and weaning time. The postoperative cardiac index and other hemodynamic parameters, including the patterns of CK-MB, did not show statistically significant differences. In the tissue samples there were an equal number of patients who developed apoptosis after the cross-clamp. Although the frequency of apoptosis in the control group was two times higher than in the adenosine group, this was statistically not significant., Conclusions: Adenosine enhanced blood cardioplegia could not prevent myocardial apoptosis completely. However, it seems to be that adenosine might influence the frequency of apoptosis and this needs to be considered in future investigations.

Acute myocarditis is often a self-limited process with a good outcome. Experimental animal studies have found that cardiomyocyte apoptosis occurs in severe forms of myocarditis. We studied whether cardiomyocyte apoptosis plays a role in the development of fatal acute human myocarditis. Myocardial autopsy samples from subjects who died of acute myocarditis in Finland between 1970 and 1998 were studied. Thirty-three of these cases(16 men and 17 women; 45 +/- 6 years old) were randomly selected for this study. All cases fulfilled the histopathologic Dallas criteria for myocarditis. Eight subjects who had died accidentally served as controls. Apoptotic DNA fragmentation (terminal transferase-mediated DNA nick end labeling) and activation of caspase-3 (immunohistochemistry) were detected. The mode of death was determined retrospectively from all available clinical data. In fatal myocarditis, large amounts of cardiomyocytes showed apoptotic DNA fragmentation or contained active caspase-3 (2.0 +/- 0.3% and 2.8 +/- 0.4%, respectively). In the controls, few apoptotic cardiomyocytes were found (0.008 +/- 0.003% by terminal transferase-mediated DNA nick end labeling and 0.009 +/- 0.003% by detection of active caspase-3, p <0.001 vs myocarditis). The amount of apoptosis did not correlate with the age or gender of the cases, recognized viral etiology, histologic features, or duration of disease. However, more apoptotic cardiomyocytes were detected in the subjects who had myocarditis and had died of heart failure (n = 18) than in those who had myocarditis and died suddenly of cardiac arrest (n = 15; 2.6 +/- 0.4% vs 1.1 +/- 0.2%, p <0.001). In conclusion, cardiomyocyte apoptosis is a common mechanism of myocardial damage in severe acute human myocarditis. Moreover, higher rates of cardiomyocyte apoptosis are associated with the development of fatal heart failure in acute myocarditis.

See Editorial on page 839. Background Acute heart failure is a potentially fatal manifestation of viral myocarditis. Development of myocardial damage in myocarditis involves cardiomyocyte apoptosis. Levosimendan is a novel calcium sensitizing inotropic agent with anti-apoptotic properties. We studied the feasibility of inotropic treatment with levosimendan and its effects on apoptosis in experimental acute heart failure caused by coxsackievirus myocarditis. Materials and methods Adolescent BALB/c mice were infected with myocarditic Woodruff variant of coxsackievirus B3 (2 × 104 plaque-forming units). Mice were randomized into those receiving levosimendan 0·33 mg kg−1 (total dose 1 mg kg−1 day−1) ( n = 20) or vehicle ( n = 19) given orally by gauge three times a day for 7 days after infection. Left ventricular function was evaluated by transthoracic echocardiography and the mice were euthanized on day 7. Histopathology, amount of virus in the heart (virus titration assay) and cardiomyocyte apoptosis (TUNEL assay) were studied. Uninfected untreated control mice were also studied. Results Infection resulted in histopathologically severe myocarditis and significant impairment of left ventricular function. Levosimendan treatment significantly improved ventricular function (fractional shortening 0·32 ± 0·04 vs. 0·23 ± 0·05, P = 0·005; contractility 0·60 ± 0·12 vs. 0·39 ± 0·14, P = 0·007 and myocardial performance index 0·36 ± 0·06 vs. 0·62 ± 0·15, P < 0·0001) compared with vehicle. Levosimendan also reduced cardiomyocyte apoptosis (0·26 ± 0·08% vs. 0·44 ± 0·15% in vehicle, P = 0·008), but did not have an effect on areas of myocardial necrosis or inflammation, or the amount of virus in the heart. Levosimendan treatment did not affect mortality (total mortality 63%). Conclusions Levosimendan improves ventricular function and inhibits cardiomyocyte apoptosis; therefore, it is suggested as a potentially feasible therapy in acute heart failure caused by viral myocarditis. [ABSTRACT FROM AUTHOR]