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Ferroptosis is a form of iron-dependent cell death caused by an excessive accumulation of reactive oxygen species and lipid peroxidation. The importance of ferroptosis in the occurrence and progression of various diseases is gradually being recognized; however, the exact biological effects and potential mechanisms of endothelial cell ferroptosis remain unclear. The endothelium forms the innermost layer of the blood vessels and lymphatic vessels. It acts as an important functional interface, responds to various pathological stimuli and causes endothelial dysfunction. Here, we review recent findings to elucidate the role of ferroptosis in endothelial cells under different pathophysiologic settings.

Background Left bundle branch pacing (LBBP) can produce near normalization of QRS duration. This has recently emerged as alternative technique to right ventricular pacing and His bundle pacing. Hypothesis The purpose of this study is to evaluate clinical outcomes of LBBP compared to right ventricular apical pacing (RVAP). Methods A total of 70 AVB patients with indications for ventricular pacing were retrospectively studied. LBBP was attempted in 33 patients, classified as LBBP group. The other patients were classified as RVAP group. Pacing parameters, electrocardiogram and echocardiogram characteristics, heart failure hospitalization (HFH), and atrial fibrillation (AF) were evaluated perioperatively and at follow-ups. Patients were followed in the device clinic for a minimum of 12 months and up to 24 months at a 3-6 monthly interval. Results LBBP was successful in 29 of 33(87.9%) patients while all 37 of the remaining patients successfully underwent RVAP. Paced QRS duration was significantly narrower in the LBBP group compare to RVAP(110.75 ± 6.77 ms vs. 154.29 ± 6.96 ms, p = .000) at implantation, and the difference persisted during follow-ups. Pacing thresholds (at implantation: 0.68 ± 0.22 V in the LBBP group and 0.73 ± 0.23 V in the RVAP group, p = .620) remained low and stable during follow-ups. The cardiac function in the LBBP group remained stable during follow-ups (LVEF%:55.08 ± 4.32 pre-operation and 54.17 ± 4.34 at the end of follow-up, p = .609), and better than RVAP group (LVEF%: 54.17 ± 4.34 vs. 50.14 ± 2.14, p = .005). Less HFH was observed in the LBBP group (2/29,6.89%) compared to RVAP group (10/37,27.03%). Conclusions The present investigation demonstrates the safety and feasibility of LBBP that produces narrower paced QRS duration than RVAP. LBBP is associated with reduction in the occurrence of pacing-induced left ventricular dysfunction and HFH compared to RVAP in patients requiring permanent pacemakers.

Diabetes mellitus (DM) has a negative impact on clinical outcomes for patients with myocardial infarction. The aim of the present study was to assess whether decreased myocardial levels of Sirtuin1 (Sirt1) contribute to the increased susceptibility of the diabetic myocardium to ischemia/reperfusion (I/R) injury. In vivo, myocardial levels of Sirt1 expression and activity were decreased in mice with STZ-induced DM. Increasing Sirt1 activity prevented the DM-induced exacerbation of myocardial mitochondrial fission, apoptosis and dysfunction elicited by I/R. In vitro, anoxia/reoxygenation (A/R) challenge of cardiomyocytes (CM) that were preconditioned with high glucose (HG-CM) resulted in an exacerbation of the A/R-induced mitochondrial fission, oxidant production and CM apoptosis; effects reversed by increasing Sirt1 protein/activity. Inhibition of Drp1 prevented the exacerbated CM mitochondrial fission and oxidant production after A/R challenge of HG-CM. Decreased Sirt1 in HG-CM was associated with decreased Akt phosphorylation. Inhibition of Akt had no effect on CM Sirt1 levels, but further increased Drp1 activation. Increasing Sirt1 levels prevented the decrease in Akt phosphorylation and Drp1 activation in A/R challenged HG-CM. In conclusion: our data indicate that the increased vulnerability of the diabetic myocardium to I/R-induced apoptosis/dysfunction is attributable, in part, to decreased myocardial Sirt1 activity which leads to a decrease in Akt activation, an increase in Drp1 activity, culminating in excessive mitochondrial fission and ROS production.

Interleukin-33 (IL-33), a new member of the IL-1 cytokine family, has cardiac protective effect in many circumstances. The aims of present study are to assess whether IL-33 can protect cardiomyocytes from doxorubicin (DOX)-induced apoptosis and the mechanism involved in the protection. Cardiomyocytes derived from either wild-type or c-Jun N-terminal kinase deficient (JNK −/- ) mice were challenged with DOX (1 μM) with or without IL-33 (10 ng/ml). Myocyte apoptosis was assessed by measuring Caspase 3 activity, fragmented DNA and the TUNEL staining. In addition, cardiomyocyte reactive oxygen species (ROS) was assessed by measuring 2′,7′-dichlorofluorescin diacetate (DCFDA); apoptosis signal-regulating kinase 1(ASK1) and JNK phosphorylation were assessed with western blot analysis. Treatment of cardiomyocyes with DOX resulted in ROS generation, ASK1 and JNK phosphorylation and myocyte apoptosis. IL-33 inhibited the DOX-induced ROS, prevented ASK1 and JNK phosphorylation and attenuated the DOX-induced myocyte apoptosis. Genetic inhibition of ASK1 (ASK1 siRNA transfection) and JNK (JNK −/- ) ameliorated the cardiac-protective effect of IL-33. Moreover, inhibition of ASK1 prevented the DOX-induced phosphorylation of JNK, while inhibition of JNK showed no effect on DOX-induced ASK1 phosphorylation. Our study indicates that: 1) ASK1/JNK signaling pathway is involved in DOX-induced cardiomyocyte apoptosis; 2) IL-33 protects cardiomyocytes from DOX-induced myocyte apoptosis through inhibition of the ASK1/JNK signaling pathway. IL-33 may have therapeutic potential for DOX-induced cardiac injury.

Background Doxorubicin (DOX) is an anti-tumor agent that is widely used in clinical setting for cancer treatment. The application of the DOX, however, is limited by its cardiac toxicity which can induce heart failure through an undefined mechanism. Mitofusin 2 (Mfn2) is a mitochondrial GTPase fusion protein that is located on the outer membrane of mitochondria (OMM). The Mfn2 plays an important role in mitochondrial fusion and fission. The aim of this study is to identify the role of the Mfn2 in DOX-induced cardiomyocyte apoptosis. Methods Cultured neonatal rat cardiomyocytes were used in this study. Mfn2 expression in cardiomyocytes was determined after the cardiomyocytes were challenged with DOX. Cardiomyocyte mitochondrial fission, mitochondrial reactive oxygen species (ROS) production was assessed with mitochondrial fragmentation and MitoSOX fluorescence probe, respectively. Cardiomyocyte apoptosis was determined with caspase3 activity and TUNEL staining. Results Challenging of the cardiomyocytes with DOX resulted in increasing in cardiomyocyte oxidative stress and apoptosis. In addition, levels of Mfn2 in cardiomyocytes were decreased after the cells were challenged with DOX which was associated with increased mitochondrial fission (fragmentation) and mitochondrial ROS production. An increase in cardiomyocyte levels of Mfn2 attenuated the DOX-induced increase in mitochondrial fission and prevented cardiomyocyte mitochondrial ROS production. An increase in cardiomyocyte levels of Mfn2 or pretreatment of cardiomyocytes with an anti-oxidant, Mito-tempo, also prevented the DOX-induced cardiomyocyte apoptosis. Conclusion Our results indicate that DOX results in a decreased cardiomyocyte Mfn2 expression which promotes mitochondrial fission and ROS production further leads to cardiomyocyte apoptosis.

Background Several clinical trials showed inconsistent results of the effect of polyunsaturated fatty acids (PUFA) on the incidence of post-operative atrial fibrillation (POAF). The aim of this meta-analysis is to investigate the effect of PUFA on the incidence of POAF in patients undergoing cardiac surgery. Methods and results PUBMED, EMBASE, Cochrane Library, and Google Scholar databases were searched for randomized controlled trials. Statistical heterogeneity was assessed using I2 statistic and Cochran's Q statistic. The effect of PUFA on the incidence of POAF was presented as risk ratio (RR) with 95% confidence intervals (CIs) using a fixed effect model or random effect model depending on statistical heterogeneity. Subgroup analyses were conducted based on the baseline characteristics of patients, types of surgery, the ratio of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA), and the quality of the studies. Eight trials with 2687 patients were included in the analysis. Treatment with PUFA had no effect on the incidence of POAF in patients undergoing cardiac surgery compared to placebo [RR 0.86; 95% CI 0.71–1.04, p = 0.110]. Subgroup analyses showed the quality of the studies, the ratio of EPA/DHA, accompanied with diabetes might impact the effect of PUFA on POAF. No evidence of publication bias was detected. Conclusions The present analysis suggests that treatment with PUFA preoperatively has no effect on the incidence of POAF in patients undergoing open heart surgery. However, patients with diabetes might get benefits from the treatment with PUFA preoperatively.

// Jia Song 1 , Qian Liu 1 , Han Tang 1 , Aibin Tao 1, 2 , Hao Wang 1 , Raymond Kao 2 , Tao Rui 1, 2, 3 1 Division of Cardiology, Department of Medicine, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China 2 Critical Illness Research, Lawson Health Research Institute, London, Ontario, N6A 4G5, Canada 3 Departments of Medicine, Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, N6A 4G5, Canada Correspondence to: Tao Rui, email: trui@uwo.ca Keywords: cardiomyocyte, HMGB1, PI3Kγ, Akt, diabetes mellitus Received: August 29, 2016 Accepted: October 28, 2016 Published: November 04, 2016 ABSTRACT Background: The high mobility group box 1 (HMGB1) protein mediates the cardiomyocyte–cardiac fibroblast interaction that contributes to induction of myocardial fibrosis in diabetes mellitus (DM). In the present study, we aim to investigate the intracellular signaling pathway that leads to cardiomyocyte HMGB1 expression under a diabetic environment. Results: HMGB1 expression is increased in high concentration of glucose (HG)-conditioned cardiomyocytes. Challenging cardiomyocytes with HG also increased PI3Kγ and Akt phosphorylation. Inhibition of PI3Kγ (CRISPR/Cas9 knockout plasmid or AS605240) prevented HG-induced Akt phosphorylation and HMGB1 expression by the cardiomyocytes. In addition, inhibition of Akt (Akt1/2/3 siRNA or A6730) attenuated HG-induced HMGB1 production. Finally, challenging cardiomyocytes with HG resulted in increased reactive oxygen species (ROS) production. Treatment of cardiomyocytes with an antioxidant (Mitotempo) abolished HG-induced PI3Kγ and Akt activation, as well as HMGB1 production. Materials and Methods: Isolated rat cardiomyocytes were cultured with a high concentration of glucose. Cardiomyocyte phosphatidylinositol 3-kinase gamma (PI3Kγ) and Akt activation were determined by Western blot. Cardiomyocyte HMGB1 production was evaluated with Western blot and enzyme-linked immunosorbent assay (ELISA), while cardiomyocyte oxidative stress was determined with a DCFDA fluorescence probe. Conclusions: Our results suggest that the cardiomyocytes incur an oxidative stress under diabetic condition, which subsequently activates the PI3Kγ/Akt cell-signaling pathway and further increases HMGB1 expression.

The NLRP3 inflammasome is an intracellular multiple-protein complex that controls the maturation and release of interleukin (IL)-1β and IL-18. Endogenous carbon monoxide (CO) is anti-inflammatory. The aim of this study was to assess the effects/mechanisms of CO-releasing molecule-3 (CORM-3)-dependent modulation of the NLRP3 inflammasome in cardiac fibroblasts (CF) and its effect on myocardial function in sepsis. CF were treated with CORM-3 or inactive CORM-3 (iCORM-3) before NLRP3 inflammasome priming with lipopolysaccharides (LPS) or following activation with adenosine triphosphate (ATP). In parallel, cardiomyocytes (CM) were challenged with supernatants of LPS/ATP-stimulated CF or a cytokine mixture (Cyto-mix) containing IL-1β, IL-18, and HMGB1. In vivo, mice were treated with CORM-3 before or after LPS to induce sepsis (endotoxemia). Pretreatment of CF with CORM-3 prevented an LPS-induced increase in NLRP3 and pro-IL-1β expression. Treatment of CF with CORM-3 before ATP prevented ATP-induced activation of the NLRP3 inflammasome. Challenging CF with LPS/ATP promoted NLRP3 interactions with adaptor ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), which was prevented by CORM-3. Challenging CM with supernatants of CF with LPS/ATP or Cyto-mix (IL-1β, IL-18, and HMGB1) resulted in CM apoptosis, which was attenuated with either a CORM-3 or IL-1 receptor antagonist. Finally, myocardial NLRP3 inflammasome activation and myocardial dysfunction in septic mice were abolished by CORM-3. In NLRP3-deficient mice with sepsis, CORM-3 did not show additional benefits in improving myocardial function. Our results indicate that CORM-3 suppresses NLRP3 inflammasome activation by blocking NLRP3 interactions with the adaptor protein ASC and attenuates myocardial dysfunction in mice with sepsis.

Several clinical trials showed inconsistent results of the effect of isolating all versus arrhythmogenic pulmonary veins (PVs) on long-term control of atrial fibrillation (AF). We hypothesized that isolation of arrhythmogenic veins had a comparable success rate to the empiric isolation of all PVs. PUBMED, EMBASE, and the Cochrane Library were searched for randomized controlled trials and nonrandomized, observational studies. The efficacy and adverse events of isolating all versus arrhythmogenic PVs were presented as risk ratio (RR) with 95 % confidence intervals (CIs), and weighted mean differences and 95 % CIs were calculated to compare the procedure time and fluoroscopic time between the isolation all PVs and arrhythmogenic PVs. Six trials with 658 patients were included in the analysis. Isolation of arrhythmogenic PVs was as efficacious as empiric isolation of all PVs in achieving long-term AF control (RR, 0.96; 95 % CI, 0.87–1.05; p = 0.36). Isolation of arrhythmogenic PVs group had shorter procedure time, fluoroscopic time and fewer adverse events than the isolation of all PVs group. The present analysis suggests that isolation of arrhythmogenic veins had a comparable long-term success rate, shorter procedure time, fluoroscopic time, and fewer adverse events than the empiric isolation of all PVs.

Diabetic cardiomyopathy (DiCM) is characterized by myocardial fibrosis and dysfunction. In rodent models of diabetes myocardial HMGB1 increases while IL-33 decreases. The major cardiac cell type expressing HMGB1 is the myocyte while the primary IL-33 expressing cell is the fibroblast. The aim of this study was to delineate the extracellular communication pathway(s) between cardiomyocytes and fibroblasts that contributes to murine DiCM. The streptozotocin (STZ)-induced murine model of diabetes and a cardiomyocyte/fibroblast co-culture challenged with high glucose were used. In STZ mice, myocardial HMGB1 expression was increased while IL-33 expression decreased (immunofluorescence and Western blot). In addition, STZ mice had an increased myocardial collagen deposition and myocardial dysfunction (pressure-volume loop analysis). An HMGB1 inhibitor (A-box) or exogenous IL-33 prevented the myocardial collagen deposition and dysfunction. In the cardiomyocyte/fibroblast co-culture model, HG increased cardiomyocyte HMGB1 secretion, decreased fibroblast IL-33 expression, and increased fibroblast collagen I production. Further, using A-box and HMGB1 shRNA transfected myocytes, we found that cardiomyocyte-derived HMGB1 dramatically potentiated the HG-induced down-regulation of IL-33 and the increase in collagen I expression in the fibroblasts. The potentiating effects of the cardiomyocytes was diminished when toll-like receptor 4 deficient (TLR4−/−) fibroblasts were co-cultured with wild-type myocytes. Finally, TLR4−/− mice with diabetes had increased myocardial expression of HMGB1, but failed to down-regulate IL-33. The diabetes-induced myocardial collagen deposition and cardiac dysfunction were significantly attenuated in TLR4−/− mice. In conclusion, our findings support a role for “cardiomyocyte HMGB1–fibroblast TLR4/IL-33 axis” in the development of myocardial fibrosis and dysfunction in a murine model of diabetes.

Summary Background Several clinical trials have shown inconsistent results regarding the effect of electrode positions on the success of electrical cardioversion. Aims The aim of this meta-analysis was to investigate the effect of the anterior-posterior electrode position on the success of electrical cardioversion in patients undergoing external electrical cardioversion for atrial fibrillation. Methods Pubmed, EMBASE, the Cochrane Library and the Chinese National Knowledge Infrastructure were searched for randomized controlled trials. The effect of the anterior-posterior electrode position on cardioversion success is presented as a risk ratio with 95% confidence interval. Results Ten trials with 1281 patients were included in the analysis. The anterior-posterior electrode position had no advantages in terms of success of electrical cardioversion for atrial fibrillation compared with the anterior-lateral electrode position (risk ratio 1.02, 95% confidence interval 0.96–1.09; P = 0.50). Subgroup analysis showed that patients with a left atrium diameter ≤ 45 mm and lone atrial fibrillation might derive benefits from the anterior-posterior electrode position in terms of success of cardioversion. No evidence of publication bias was detected. Conclusions The present analysis suggests that only patients with a left atrium diameter ≤ 45 mm and lone atrial fibrillation might derive benefits from the anterior-posterior electrode position compared with the anterior-lateral electrode position during external electrical cardioversion for atrial fibrillation. However, there was insufficient evidence to support any advantages for the anterior-posterior electrode position in other situations.