[Effects of pretreatment with metoprolol on cardiomyocyte apoptosis and caspase-8 activation after coronary microembolization in rats].

OBJECTIVE: To investigate the effects of metoprolol on cardiomyocyte apoptosis and caspase-8 activation after coronary microembolization(CME) in rats. METHODS: Adult rats were randomly assigned into CME group (intraventricular injection of 3000 microspheres with 42 µm in diameter), sham-operated group (0.1 ml saline) and CME plus metoprolol group (pretreatment with 3 bolus metoprolol 2.5 mg/kg intravenous injection at 10 minutes interval at 30 minutes before microspheres injection, n = 15, each group). Cardiac function was evaluated by echocardiography at 6 hours post various treatments. Cardiomyocyte apoptosis was detected with TUNEL staining and the expression of caspase-3 and caspase-8 was detected with Western blot analysis. RESULTS: Compared with sham-operated group, LVEF (72.68% ± 3.26% vs. 82.64% ± 3.43%, P < 0.05), fractional shortening (FS) (37.46% ± 2.38% vs. 42.85% ± 3.25%) and cardiac output (CO) [(0.101 ± 0.006) L/min vs. (0.162 ± 0.008) L/min] were significantly reduced while left ventricular end-diastolic diameter (LVEDd) [(6.22 ± 0.17) mm vs. (5.18 ± 0.43) mm] was significantly increased in CME group (all P < 0.05). Cardiac function [LVEF:73.94% ± 4.22%, FS:38.53% ± 2.03%, CO:(0.120 ± 0.012) L/min, LVEDd:(6.18 ± 0.27) mm] was similar in CME plus metoprolol group compared to CME group (all P > 0.05). The cardiomyocytes apoptosis rates (3.19% ± 1.23% vs. 0.18% ± 0.10%) and the levels of activated caspase-3 and caspase-8 proteins were significantly increased in CME group than in sham-operated group (all P < 0.05). The cardiomyocyte apoptosis rate (1.32% ± 0.28%) and the levels of activated caspase-3 and caspase-8 proteins were significantly lower in CME plus metoprolol group than in CME group (all P < 0.05). CONCLUSIONS: Metoprolol pretreatment reduced post-CME myocardial apoptosis possibly through downregulating death receptor-mediated apoptotic pathway.

Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats.

OBJECTIVE: To explore the effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization (CME) in rats. METHODS: Forty rats were randomly divided into four groups (n=10 each): a sham operation (control) group, CME plus saline (CME) group, CME plus metoprolol (metoprolol) group and caspase-9 inhibitor Z-LEHD-FMK (ZLF) group. CME was induced by injecting 3000 polyethylene microspheres (42 µm diameter) into the left ventricle during a 10 s occlusion of the ascending aorta. Echocardiography, terminal deoxynucleotidyl transferase dUTP nick end labelling and Western blotting were used to evaluate cardiac function, apoptosis and activation of caspase-9/caspase-3, respectively, 6 h after CME. RESULTS: The echocardiographic parameters of left ventricular function were significantly decreased in the CME group compared with the control group (P<0.05); however, the metoprolol group and ZLF group showed significantly improved cardiac function compared with CME alone (P<0.05). Compared with the control group, the myocardial apoptosis rate and the levels of activated caspase-9 and -3 increased significantly in the CME group (P<0.05). Again, these effects were ameliorated by metoprolol and ZLF (P<0.05). CONCLUSIONS: The present study demonstrates that metoprolol and ZLF can protect the rat myocardium during CME by inhibiting apoptosis and improving cardiac function, likely by inhibiting apoptosis/ mitochondrial apoptotic pathway. These results suggest that antiapoptotic therapies may be useful in treating CME.

Drug-eluting stents vs. intracoronary brachytherapy for in-stent restenosis: a meta-analysis.

BACKGROUND: It has been reported that drug-eluting stents (DES) were superior to intracoronary brachytherapy (ICBT) in patients with in-stent restenosis (ISR). However, it is unknown whether there might be differences between DES and ICBT in terms of efficacy and safety in large sample size and long-term follow-up. HYPOTHESIS: The aim of this study was to determine whether DES implantation remains favorable in large sample size and long-term follow-up when compared with ICBT among patients with ISR. METHODS: We conducted a search in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials without language restrictions. A meta-analysis of 1942 cases from 12 controlled trials of DES vs ICBT for ISR was performed. RESULTS: Drug-eluting stents were significantly more effective in reducing target-vessel revascularization (TVR) (odds ratio [OR]: 0.44, 95% confidence interval [CI]: 0.23-0.81, P = 0.009) and binary restenosis (OR: 0.34, 95% CI: 0.26-0.46, P<0.00001) compared with ICBT at midterm follow-up. There were no significant differences between DES and ICBT in cardiac death, myocardial infarction (MI), and late stent thrombosis at midterm follow-up. A statistical significance has been found between the 2 groups in TVR (OR: 0.61, 95% CI: 0.43-0.86, P = 0.005) at long-term follow-up. There were no significant differences in cardiac death and MI between the 2 groups at long-term follow-up. CONCLUSIONS: These findings provide evidence that DES is superior to ICBT for the treatment of ISR in TVR and binary restenosis reduction, but not in cardiac death, MI, and late stent thrombosis reduction. © 2011 Wiley Periodicals, Inc. Yong-Guang Lu, MD, and Yan-Mei Chen, MD, contributed equally to this work. The authors have no funding, financial relationships, or conflicts of interest to disclose.

[Cardiomyocyte apoptosis and death receptor pathway in a rat model of coronary microembolization].

OBJECTIVE: To investigate the dynamic changes of cardiomyocyte apoptosis and the role of death receptor apoptotic pathway in a rat model of coronary microembolization (CME). METHODS: Adult rats were randomized to coronary microembolization (CME group, n = 63) or sham-operated group (S group, n = 55). CME model was established by aortic injection of 0.1 ml microspheres (42 microm, 3 x 10(4)/ml) into the left ventricle when the ascending aorta was temporarily clamped.S group received 0.1 ml saline injection and survived rats were randomly examined at 0, 3, 6, 12 and 24 hour post CME (n = 10 each). Heart function was evaluated by echocardiography. Myocardium sample was stained with hematoxylin-eosin and hematoxylin-basic fuchsin-picric acid to detect infarct areas. Cardiomyocyte apoptosis was detected with TUNEL staining. The expression of caspase-3 and caspase-8 was measured by Western blot analysis. RESULTS: Compared with S group, the left ventricular ejection fraction was significantly decreased and left ventricular end-diastolic diameter was significantly increased in CME group (all P < 0.05) except 0 hour CME group. The infarct sizes were similar in 3 hour, 6 hour, 12 hour, and 24 hour CME groups (P > 0.05). The apoptosis index (AI) in CME group were significantly higher at each time point compared to S group (P < 0.05) except 0 hour CME group and peaked at 6 hours. Apoptotic cardiomyocytes were found mainly in the myocardial microinfarcted area and border zones. The relative expression of caspase-3 and caspase-8 in CME group were both significantly increased at 3 hours and peaked at 6 hour post CME (P < 0.05). CONCLUSION: Cardiomyocytes apoptosis was significantly increased after coronary microembolization via activating death receptor apoptotic pathway in this coronary microembolization model.