Ischemic postconditioning, a simple mechanical maneuver at the onset of reperfusion, reduces infarct size after ischemia/reperfusion. After its first description in 2003 by Zhao et al. numerous experimental studies have investigated this protective phenomenon. Whereas the underlying mechanisms and signal transduction are not yet understood in detail, infarct size reduction by ischemic postconditioning was confirmed in all species tested so far, including man. We have now reviewed the literature with focus on experimental models and protocols to better understand the determinants of protection by ischemic postconditioning or lack of it. Only studies with infarct size as unequivocal endpoint were considered. In all species and models, the duration of index ischemia and the protective protocol algorithm impact on the outcome of ischemic postconditioning, and gender, age, and myocardial temperature contribute.
I schemic postconditioning (IPoC) reduces infarct size by attenuation of reperfusion injury 1 and is operative in all species studied so far, including humans. 2,3 The phosphorylation of RISK (reperfusion injury salvage kinases), ie, phosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT), 4,5 mitogen-activated protein kinase kinase/extracellular signal regulated kinase (ERK) (MEK1/2-ERK1/2), 6 p70 ribosomal S6 protein kinase (P70S6K), and glycogen synthase kinase (GSK)3 was proposed to be causal for protection by IPoC. 4 -7 Activation of sarcolemmal receptors projects through parallel pathways of either PI3K-AKT or MEK1/2-ERK1/2 onto P70S6K and ultimately on GSK3, which, when phosphorylated, inhibits mitochondrial permeability transition pore opening. 8 Whether specific RISK kinases or a concert of different RISK kinases confer the protection by postconditioning is less clear. 4,6,7,9,10 In 2 studies, there was RISK phosphorylation but no protection by postconditioning. 11,12 Most studies on the role of RISK in postconditioning were performed in rodent hearts, 4,6,7 which, apart from species differences to larger mammals including humans, may pose methodological limitations: the small amount of tissue available for Western blots permits neither determination of baseline values nor that of infarct size in an individual heart. The association of RISK phosphorylation with less infarction could therefore be cause or consequence of the observed protection.The present study evaluates the role of RISK for postconditioning in pigs. With regard to size, coronary anatomy, and heart rate, the pig heart resembles more closely the human heart than smaller species, and it permits taking multiple biopsies at different time points and determining infarct size in an individual heart. Materials and MethodsThe experiments were performed in an established pig model of regional ischemia/reperfusion with infarct size determination and Western blot analysis (see the expanded Materials and Methods section in the online data supplement, available at http://circres. ahajournals.org). Protocol 1IPoC (nϭ13) was induced by 6 cycles of 20 seconds of reperfusion and 20 seconds of reocclusion at the onset of reperfusion. Immediate full reperfusion (IFR) (nϭ15) was established for comparison. Protocol 2In 8 animals, 4 with IPoC (B-IPoC) and 4 with IFR (B-IFR), the 2 major upstream RISK pathways PI3K-AKT and MEK1/2-ERK1/2 were blocked before the onset of reperfusion (see the online data supplement). StatisticsData are meansϮSEM. Data were analyzed by 2-way ANOVA for repeated measures with least significant difference tests or doublesided t tests; PϽ0.05 was considered significant.
Ivabradine's protection goes beyond heart rate reduction.
Background: Patients in palliative care need rapid-acting pharmacological options for psychological distress. Nmethyl-D-aspartate antagonist ketamine is known to have a fast onset of anti-depressant and anxiolytic action. Its Senantiomer S-ketamine (or esketamine) is an analgesic used as a routine treatment for refractory pain as an intravenous infusion (0.25 mg/kg over 45 min). This study investigates whether S-ketamine pain therapy has a positive impact on psychological distress caused by anxiety and depression in palliative care. Methods: Patient routine data from a palliative care unit of a tertiary care hospital were used in a retrospective analysis after positive ethics approval. Eight patients, who received analgesic S-ketamine treatment, were compared to a control group matched by gender and age. The main analysis was conducted using three-way mixed MANOVA followed by two-way mixed ANOVA. Target variables were the values for anxiety and depression in the state-trait anxiety-depression inventory STADI. The predictor variables were the time of measurement before (T1) and after (T2) S-ketamine application and group membership. Results: Comparison of the S-ketamine group (n = 8; 4 male, 4 female; average age 52 years) with the control group (n = 8; 3 male, 5 female; average age 55 years) revealed a significant multivariate effect on anxiety and depression F(1, 14) = 4.78; p = 0.046; r = 0.50. The univariate comparisons showed a significant reduction of the anxiety scores from T1 to T2 in the S-ketamine group compared to the control group F(1, 14) = 10.14; p = 0.007; r = 0.65. With regard to depression, there was no significant reduction from T1 to T2 in the group comparison F(1, 14) = 1.60; p = 0.23; r = 0.32. No long-lasting effects on pain were found. Conclusions: Our findings show that psychological distress of patients in palliative care may improve after a single administration of S-ketamine, which mainly alleviates anxiety in those patients. Limitations of this study arise from non-randomization, retrospective analysis and low sample size. Therefore, further prospective and ideally randomized studies are necessary.
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