Search

Background: As an indicator of cardiac autonomic nervous activity, heart rate variability (HRV) is closely linked to premature ventricular complexes (PVCs). However, its role in patients with frequent PVCs originating from the ventricular outflow tract remains unclear. Hypothesis: Here, we hypothesize that there may be alterations in HRV among patients with frequent PVCs originating from the ventricular outflow tract, which could play significant roles in the management of such patients. Methods: A retrospective study was conducted, including 106 patients with frequent outflow tract PVCs and 106 healthy participants as controls. HRV was assessed based on the 24‐hour Holter recording. The originating foci of PVCs were identified during radiofrequency catheter ablation. Results: Patients with frequent outflow tract PVCs exhibited decreased levels of high frequency (HF), standard deviation of all NN intervals, and standard deviation of the average NN intervals, but increased ratios of low frequency to HF (LF/HF ratio), even after propensity score‐matched analysis. Further investigation revealed that patients with PVCs originating from right ventricular outflow tract (RVOT) had much higher LF/HF ratios. Multivariate logistic regression analysis demonstrated that the LF/HF ratio was independently associated with PVCs originating from RVOT. Receiver operating characteristics curve indicated that the LF/HF ratio effectively determined the origin of PVCs (the area under the curve = 0.75, p <.001). Conclusions: Patients with frequent outflow tract PVCs exhibited impaired HRV. Additionally, the LF/HF ratio played a significant role in determining the origin of outflow tract PVCs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most common gynecological malignancies in women worldwide with a poor survival rate. Cinnamaldehyde (CA), a bioactive substance isolated from cinnamon bark, is a natural drug and has shown that it can inhibit the progression of other tumors. However, the role of CA in ovarian cancer and its mechanism is poorly understood. In this study, wound healing assays, plate cloning, CCK-8, and transwell assays were used to determine cell proliferation and invasion. Western blot and flow cytometry were used to detect apoptosis levels. Western blot and immunofluorescence were used to detect changes in cellular EMT levels. The Western blot was used to detect levels of the PI3K/AKT signaling pathway. In vivo , we established a subcutaneous transplantation tumor model in nude mice to verify the role of CA in the progression and metastasis of ovarian cancer. Our data showed that in vitro CA was able to inhibit the cell viability of ovarian cancer. The results of scratch assay and transwell assay also showed that CA inhibited the proliferation and invasion ability of A2780 and SKOV3 cells. In addition, CA promoted apoptosis by increasing the expression of cleaved-PARP and cleaved-caspase 3 in ovarian cancer cells. Mechanistically, we found that CA inhibited the EGF-induced PI3K/AKT signaling pathway and reduced the phosphorylation levels of mTOR, PI3K, and AKT. The EGF-induced EMT process was also abolished by CA. The EMT process induced by AKT-specific activator SC79 was also suppressed by CA. Furthermore, in in vivo , CA significantly repressed the progression of ovarian cancer as well as liver metastasis. In all, our results suggest that CA inhibits ovarian cancer progression and metastasis in vivo and in vitro and inhibits EGF-induced EMT processes through the PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sepsis/endotoxemia activates the NLRP3 inflammasome of macrophages leading to the maturation and release of IL-1β, an important mediator of the inflammatory response. Reactive oxygen species have been implicated in NLRP3 inflammasome activation. Further, our preliminary studies indicated that LPS challenge of cardiac fibroblasts could phosphorylate protein kinase R (PKR) on threonine 451 and increase message for pro-IL-1 β. Thus, the major aim of the present study was to address the role of PKR and the oxidant, peroxynitrite, in the two-tiered function of the NLRP3 inflammasome (priming and activation). Materials and Methods: Isolated murine fibroblasts were primed with LPS (1 μg/ml) for 6 h and subsequently activated by an ATP (3 mM) challenge for 30 min to induce optimum functioning of the inflammasome. Increased levels of NLRP3 and pro-IL-1β protein (Western) were used as readouts for inflammasome priming, while activation of caspase 1 (p20) (Western) and secretion of IL-1β (ELISA) were indicative of inflammasome activation. Results: Inhibition of PKR (PKR inhibitor or siRNA) prior to priming with LPS prevented the LPS-induced increase in NLRP3 and pro-IL-1β expression. Further, inhibition of PKR after priming, but before activation, did not affect NLRP3 or pro-IL-1β protein levels, but markedly reduced the activation of caspase 1 and secretion of mature IL-1β. In a similar fashion, a peroxynitrite decomposition catalyst (Fe-TPPS) prevented both the priming and activation of the NLRP3 inflammasome. Finally, pretreatment of the fibroblasts with Fe-TPPS prevented the LPS-induced PKR phosphorylation (T451). Conclusion: Our results indicate that peroxynitrite-/PKR pathway modulates priming and activation of NLRP3 inflammasome in LPS/ATP challenged cardiac fibroblasts. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Diabetes Mellitus results in down-regulation of myocardial Sirt1. • Reduced Sirt1 in cardiomyocytes decreases Akt phosphorylation that increases Drp1 activation after ischemia/reperfusion. • Increased Drp1 activation induces mitochondrial fission, oxidant stress and exaggerates ischemia/reperfusion-induced myocardial injury. Abstract 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Cardiac sympathetic nerve system (SNS) might play an important role in arrhythmogenesis of arrhythmogenic cardiomyopathy (ACM). This study aims to assess the activity of cardiac SNS in ACM patients by heart rate variability (HRV), and to investigate its predictive value for sustained ventricular tachycardia (sVT)., Methods: A total of 88 ACM patients and 65 sex- and age- matched healthy participants were enrolled. The time domain measures were used to evaluate the activity of cardiac SNS. An independent cohort with 48 ACM patients was as the validation cohort., Results: ACM patients had lower levels of standard deviation of all NN intervals (SDNN) [118.0 (90.3, 136.8) vs. 152.0 (132.5, 174.5) ms, p < 0.001] compared with healthy participants. Further analysis showed ACM patients with sVT had lower levels of SDNN than those without sVT (105.0 ± 28.1 vs. 131.8 ± 33.1 ms, p < 0.001). Multivariate logistic regression analysis showed SDNN was independently associated with sVT in ACM patients [odds ratio (OR) 0.59, 95% confidence interval (CI) (0.45-0.78), p < 0.001]. Receiver operating characteristics curve demonstrated SDNN had clinical values in predicting sVT in ACM patients [area under the curve (AUC) = 0.73, 95% CI (0.63-0.84), p < 0.001], which was verified in the validation cohort., Conclusion: The present study suggests that HRV is impaired in patients with ACM, and the SDNN level has a moderate value in risk stratification for sVT in ACM patients. In addition, the finding might provide new target for the further management of ACM with integrated traditional Chinese and western medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Zhou, Liu, Zhang, Jiang, Tang, Xie, Wu, Xie, Li, Yu, Wang, Cheng, Zhou, Chen, Fan, Zhou, Tao and Yang.)

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 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.

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 I(2) 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., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)