The role of iron overload and ferroptosis in arrhythmia pathogenesis.

Ferroptosis is a newly discovered form of programmed cell death triggered by intracellular iron overload, which leads to the accumulation of lipid peroxides in various cells. It has been implicated in the pathogenesis and progression of various diseases, including tumors, neurological disorders, and cardiovascular diseases. The intricate mechanism underlying ferroptosis involves an imbalance between the oxidation and antioxidant systems, disturbances in iron metabolism, membrane lipid peroxidation, and dysregulation of amino acid metabolism. We highlight the key molecular mechanisms governing iron overload and ferroptosis, and discuss potential molecular pathways linking ferroptosis with arrhythmias.

SGLT2i­treated heart failure patients with a reduced ejection fraction: A meta­analysis.

The aim of this study was to investigate the effects of SGLT2 inhibitors (SGLT2i) on patients with heart failure (HF) and reduced ejection fraction, with or without diabetes. A systematic review of randomized controlled trials (RCTs) was conducted, comparing SGLT2i to a placebo for HF patients. Relevant studies from PubMed, Web of Science, and EMBASE were searched from inception to July 2021, without any language restrictions. The pooled effect was estimated using the odds ratio (OR) and 95% confidence interval (CI). Depending on the heterogeneity test results, either random effects or fixed effects models were selected to estimate the pooled effects. Sensitivity analysis was conducted by gradually removing each study to evaluate the results' stability. A total of 5 RCT studies were included in the analysis. The fixed-effects model demonstrated that the patients in the SGLT2i group had a lower risk of hospitalization for HF/cardiovascular death (OR=0.72; 95% CI, 0.67-0.78), P<0.0001; I2=0.0%, P=0.966), cardiovascular death (OR=0.84, 95% CI (0.77, 0.93), P<0.0001; I2=0.0%, P=0.633), hospitalization for HF (OR=0.69, 95% CI (0.63, 0.75), P<0.0001; I2=0.0%, P=0.933), and all-cause mortality (OR=0.79, 95% CI (0.71, 0.89), P<0.0001; I2=3.3%, P=0.376) compared to the placebo group. Sensitivity analysis showed that the pooled effect value remained stable within the corresponding range, even after each study was gradually removed. In conclusion, SGLT2i can reduce the risk of HF hospitalization, cardiovascular death, and all-cause mortality in patients with HF and a reduced ejection fraction, regardless of the presence or absence of diabetes.

Acute myocardial infarction with normal electrocardiogram and biomarkers of cardiac injury: A case report.

Patients with AMI usually present with the specific changes for electrocardiogram (ECG) and biomarkers of cardiac injury. Here, we present a rare case with chest pain and normal ECG and biomarkers of cardiac injury. Emergent coronary angiography revealed an occlusion of proximal left anterior descending coronary artery. The patient was diagnosed with AMI, and his symptom relieved after implantation of drug-eluting stents. Caution should be exercised for the exclusion of AMI in patients with chest pain and both normal ECG and biomarkers of cardiac injury.

Targeting Autophagy in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common type of arrhythmia in clinical practice, and its incidence is positively correlated with risk factors that include advanced age, hypertension, diabetes, and heart failure. Although our understanding of the mechanisms that govern the occurrence and persistence of AF has been increasing rapidly, the exact mechanism of AF is still not fully understood. Autophagy is an evolutionarily highly conserved and specific physiological process in cells that has been suggested as a potential therapeutic target for several cardiovascular diseases including the pathophysiology of AF. The present article provides an updated review of the fast-progressing field of research surrounding autophagy in AF, and how regulating autophagy might be a therapeutic target to reduce the incidence of AF.

Golgi a-mannosidase II mediates the formation of vascular smooth muscle foam cells under inflammatory stress.

INTRODUCTION: Vascular smooth muscle cells (VSMCs)-based foam cell formation is a crucial factor in the atherosclerosis process. We aimed to explore the mechanism of Golgi a-mannosidase II (GMII) effects on the VSMCs-based foam cell formation. MATERIAL AND METHODS: VSMCs were exposed to different concentrations of low-density lipoproteins (LDLs), lipopolysaccharide (LPS), and/or GMII inhibitor (swainsonine). The qRT-PCR and western blot were used for expression analysis. Oil Red O staining was used to verify changes of lipid droplets in VSMCs. The translocation of the SCAP from the endoplasmic reticulum (ER) to Golgi was detected by immunofluorescence (IF). RESULTS: LPS disrupted the LDLs-mediated regulation of LDL receptor (LDLr) and increased intracellular cholesterol ester, which was inversely inhibited by swainsonine. The activity of a-mannosidase II and GMII expression were decreased by LDLs but increased by the addition of LPS. Conversely, LPS-induced enhancement was reversed by swainsonine. Additionally, swainsonine reversed the LPS-induced increase of intracellular lipid droplets in the presence of LDLs. Expression analysis demonstrated that LDLr, SCAP, and SREBP2 were up-regulated by LPS, but reversed by swainsonine in LDLs-treated cells. IF staining revealed that swainsonine inhibited the translocation of SCAP to Golgi under inflammatory stress. CONCLUSIONS: Collectively, swainsonine restrained LDLr expression to suppress the formation of VSMCs-based foam cells by reducing SREBP2 and SCAP under inflammatory stress conditions, suggesting that GMII contributes to the formation of VSMCs-based foam cells under inflammatory stress.

A Novel Mutation in the KCNH2 Gene Associatedwith Long QT Syndrome: A Case Report.

OBJECTIVE: Long QT syndrome is a cardiovascular disease with a prolonged QT interval. CASE REPORT: We report a 22-year-old woman presenting with frequent syncopal episodes two months after childbirth. Electrocardiography showed a sinus rhythm, QT interval prolongation, and Torsade de Pointes. Her mother had experienced an episode of syncope, but her father had not. Genetic analyses revealed that a new mutation in the KCNH2 gene, the c.2108dupA mutation (p.H703Qfs*20, exon8, M_000238), was found in the patient and in her mother and sister. CONCLUSION: The c.2108dupA mutation (p.H703Qfs*20, exon8, M_000238) is the first reported case of a KCNH2 mutation at this site.

Atorvastatin Enhances Foam Cell Lipophagy and Promotes Cholesterol Efflux Through the AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway.

ABSTRACT: Foam cells are the main pathological components of atherosclerosis. Therapies reducing foam cell formation can effectively prevent atherosclerotic diseases and cardiovascular events. Beyond lowering plasma cholesterol levels, the pleiotropic functions of statins in atherosclerosis have not been fully elucidated. In the present study, atorvastatin reduced cholesterol content and increased cholesterol efflux from foam cells in a concentration-dependent manner. Atorvastatin (10 µM) inhibited foam cell formation within 48 hours. Furthermore, we found that atorvastatin inhibited foam cell formation by promoting lipophagy, which was manifested by increased autophagy-related gene 5 (Atg5) expression, elevated ratio of microtubule-associated protein1 light chain 3 (LC3) II to LC3I, reduced p62 expression, and increased LC3 and lipid droplets colocalization in foam cells treated with atorvastatin. The autophagy inducer, rapamycin (Rap), did not increase the lipophagy enhancement effect of atorvastatin, but the autophagy inhibitor, 3-methyladenine, suppressed the effect of atorvastatin on Atg5 expression and the LC3II/LC3I ratio, as well as the increased p62 expression, suppressed lipophagy, attenuated cholesterol efflux and increased cholesterol content in foam cells. Further analysis revealed that atorvastatin promoted lipophagy by upregulating adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation, and downregulating mammalian target of rapamycin phosphorylation, whereas the AMPK inhibiter, compound C, attenuated these effects. In conclusion, atorvastatin reduced lipid accumulation and promoted cholesterol efflux by enhancing lipophagy in foam cells and thereby inhibited foam cell formation. The enhanced lipophagy of foam cells was exerted through the AMPK/mammalian target of rapamycin signaling pathway.

Clinical investigation of left ventricular pacing using coronary sinus in patients with mechanical prosthetic tricuspid valve replacement.

BACKGROUND: Although transvenous right ventricular (RV) endocardial lead placement is routine practice in clinical pacing, RV inaccessibility in certain clinical situations mandates the search for other sites. HYPOTHESIS: This study is aimed to verify whether left ventricular lead through coronary sinus is safe and efficient. METHODS: Based on a retrospective analysis of a single-center series of 4 patients with inaccessibility for RV pacing, we report on the feasibility and reliability of coronary sinus (CS) pacing via left ventricular (LV) lead, which usually is used in cardiac resynchronization therapy. Four patients with valvular heart disease and bradycardias post-mechanical prosthetic tricuspid valve replacement were studied. The LV leads were implanted into the lateral vein or great cardiac vein of the CS, and all parameters were programmed postprocedure. RESULTS: In all cases procedures yielded favorable parameters, with 1 CS dissection. At long-term follow-up, there was no threshold increase or lead dislocation. CONCLUSIONS: LV lead implantation through the CS appears safe and efficacious in patients with inaccessibility for RV pacing.

The roles of nitric oxide and hydrogen sulfide in the anti-atherosclerotic effect of atorvastatin.

AIMS: To investigate antiatherosclerosis effect of atorvastatin (ATV) in a rat atherosclerosis model, and to explore roles of nitric oxide and hydrogen sulfide (H2S) in this event. METHODS: After being fed a high-fat diet, the rats were treated with ATV, ATV combined with cystathionine-γ-lyase (CSE) inhibitor DL-propargylglycine, and ATV combined with endothelial nitric oxide synthase (eNOS) inhibitor N'-nitro-L-arginine-methyl ester hydrochloride from 9 to 12 weeks, respectively. At the end of the experiment, the animals were sacrificed. Pathologic changes of aortic arch were observed to assay the degree of atherosclerotic lesions. Serum total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol were determined. Further, nitric oxide, total nitric oxide synthase and eNOS, and H2S and CSE were also measured. RESULTS: Compared with the normal control group, serum TC, triglyceride, and LDL-C levels in the model group were significantly elevated (P < 0.05). Pathological result suggested typical atherosclerotic lesions after the high-fat diet. The serum nitric oxide, eNOS, H2S, and CSE significantly decreased (P < 0.05). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed that mRNA levels of eNOS and CSE in the aortic arch of the model rats were significantly downregulated (P < 0.05). Actually, ATV significantly ameliorated atherosclerotic lesions. ATV also significantly downregulated increased serum TC and LDL-C, and upregulated decreased serum nitric oxide and eNOS. However, it had no significant effects on serum H2S and CSE (P > 0.05). ATV combined with DL-propargylglycine significantly reduced serum H2S and CSE, and increased serum nitric oxide and eNOS as compared to single ATV treatment (P < 0.05). ATV combined with N'-nitro-L-arginine-methyl ester hydrochloride significantly increased serum TC, LDL-C, H2S, and CSE, and decreased nitric oxide and eNOS as compared to the single ATV (P < 0.05). CONCLUSIONS: ATV significantly ameliorates atherosclerotic lesions and enhances the activity of serum nitric oxide system, but not H2S system. The blockage of nitric oxide pathway, but not H2S pathway, significantly weakens antiatherosclerosis of ATV.