Prostaglandin I2 signaling prevents angiotensin II-induced atrial remodeling and vulnerability to atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.

Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression.

The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenic factor in cardiovascular diseases. The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. A total of 30 rats were randomly divided into control, ER stress inducer (tunicamycin[TN]) and ER stress inhibitor (tunicamycin+4-phenylbutyric acid [4-PBA]) groups. ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), left ventricular peaksystolic pressure(LVSP) and LV end-diastolic pressure(LVEDP). Epicardial mapping performed in vivo revealed reduced conduction velocity and increased conduction heterogeneity associated with the development of spontaneous ventricular tachycardia. Masson's trichrome staining revealed marked fibrosis in the myocardial interstitial and sub-pericardial regions, and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor transforming growth factor-ß1 (TGF-ß1), decreased mitochondrial biogenesis protein peroxlsome proliferator-activated receptor-γ coactlvator-1α （PGC-1a）, and decreased mitochondrial fusion protein mitofusin-2 (MFN2). These changes were associated with mitochondria dysfunction and connexin 43(CX43)translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodelling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA.

Electrocardiographic characteristics of diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy.

BACKGROUND: Patients receiving anthracycline-based chemotherapy (AbC) for newly diagnosed diffuse large B-cell lymphoma (DLBCL) may develop cardiac electrophysiological abnormalities. In this study, their electrocardiography (ECG) features were analyzed. METHODS: Electronic health records of patients with a diagnosis of DLBCL and treated with AbC were reviewed retrospectively. Variables from ECGs obtained around anthracycline treatment were manually measured. RESULTS: A total of 76 patients (57% males). The incidence of abnormal ECG increased from 36.8% at baseline to 48.7%, of which only the prevalence of fragmented QRS (fQRS) significantly increased after AbC (15.8% to 28.9%, P = 0.041). In comparison with baseline ECG parameters, corrected QT interval (QTc) statistically prolonged (399.95 ± 27.11 ms to 415.07 ± 31.03 ms, P < 0.001), whilst QT dispersion (QTd) significantly (41.25 ± 16.15 ms to 36.70 ± 11.84 ms, P = 0.032) decreased. CONCLUSION: In DLBCL patients receiving anthracycline-based therapies, the main ECG abnormalities detected were fQRS and QTc prolongation. Regular ECG monitoring should be carefully performed on follow-up to detect cardiotoxicity during follow-up after treatment.

Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin-induced myocardial injury.

Background: Doxorubicin is a widely used cytotoxic chemotherapy agent for treating different malignancies. However, its use is associated with dose-dependent cardiotoxicity, causing irreversible myocardial damage and significantly reducing the patient's quality of life and survival. In this study, an animal model of doxorubicin-induced cardiomyopathy was used to investigate the pathogenesis of doxorubicin-induced myocardial injury. This study also investigated a possible treatment strategy for alleviating myocardial injury through resveratrol therapy in vitro. Methods: Adult male C57BL/6J mice were randomly divided into a control group and a doxorubicin group. Body weight, echocardiography, surface electrocardiogram, and myocardial histomorphology were measured. The mechanisms of doxorubicin cardiotoxicity in H9c2 cell lines were explored by comparing three groups (phosphate-buffered saline, doxorubicin, and doxorubicin with resveratrol). Results: Compared to the control group, the doxorubicin group showed a lower body weight and higher systolic arterial pressure, associated with reduced left ventricular ejection fraction and left ventricular fractional shortening, prolonged PR interval, and QT interval. These abnormalities were associated with vacuolation and increased disorder in the mitochondria of cardiomyocytes, increased protein expression levels of α-smooth muscle actin and caspase 3, and reduced protein expression levels of Mitofusin2 (MFN2) and Sirtuin1 (SIRT1). Compared to the doxorubicin group, doxorubicin + resveratrol treatment reduced caspase 3 and manganese superoxide dismutase, and increased MFN2 and SIRT1 expression levels. Conclusion: Doxorubicin toxicity leads to abnormal mitochondrial morphology and dysfunction in cardiomyocytes and induces apoptosis by interfering with mitochondrial fusion. Resveratrol ameliorates doxorubicin-induced cardiotoxicity by activating SIRT1/MFN2 to improve mitochondria function.

Neutrophil Extracellular Traps: Potential Prothrombotic State Markers and Therapeutic Targets for Atrial Fibrillation.

BACKGROUND: Recently, the mechanism of thrombogenesis has taken a new direction with the involvement of neutrophil extracellular traps (NETs). However, little is known about the relationship between NETs and thrombogenesis in atrial fibrillation (AF). OBJECTIVE: Our study aimed to evaluate NETs in AF patients and their potential association with thrombogenesis. In addition, we studied the effect of NETs on thrombogenesis in rat models. METHODS: A total of 125 AF patients and 172 controls were studied. Spontaneous echo contrast (SEC) was examined using transesophageal echocardiography to assess the prothrombotic state. We used rapid atrial pacing (RAP) rat models to study NETs' formation and their effects on thrombogenesis. The levels of NETs were analyzed by flow cytometry. To deeply understand the regulatory mechanism of NET formation, the transcriptional characteristics of the left atrial appendage (LAA) tissue from RAP rats were analyzed. RESULTS: We found that NETs were increased significantly in AF patients and positively correlated with SEC grades. And inserting the NET level could significantly enhance the predictivity of CHA2DS2-VASc scores for the AF prothrombotic state. In the RAP models, we observed that NET levels increased significantly in the LAA and promoted thrombosis. Meanwhile, we found that these changes could be suppressed by the NET formation inhibitor. Transcriptomic analysis of the LAA tissue from RAP rats suggested that RAP might stimulate the NET formation by promoting the expression of inflammatory cytokine and adhesion genes. CONCLUSION: NETs may constitute useful thrombogenesis risk markers in AF patients and provide a potential therapeutic strategy for AF management.

Role of Heat Shock Proteins in Atrial Fibrillation: From Molecular Mechanisms to Diagnostic and Therapeutic Opportunities.

Heat shock proteins (HSPs) are endogenous protective proteins and biomarkers of cell stress response, of which examples are HSP70, HSP60, HSP90, and small HSPs (HSPB). HSPs protect cells and organs, especially the cardiovascular system, against harmful and cytotoxic conditions. More recent attention has focused on the roles of HSPs in the irreversible remodeling of atrial fibrillation (AF), which is the most common arrhythmia in clinical practice and a significant contributor to mortality. In this review, we investigated the relationship between HSPs and atrial remodeling mechanisms in AF. PubMed was searched for studies using the terms "Heat Shock Proteins" and "Atrial Fibrillation" and their relevant abbreviations up to 10 July 2022. The results showed that HSPs have cytoprotective roles in atrial cardiomyocytes during AF by promoting reverse electrical and structural remodeling. Heat shock response (HSR) exhaustion, followed by low levels of HSPs, causes proteostasis derailment in cardiomyocytes, which is the basis of AF. Furthermore, potential implications of HSPs in the management of AF are discussed in detail. HSPs represent reliable biomarkers for predicting and staging AF. HSP inducers may serve as novel therapeutic modalities in postoperative AF. HSP induction, either by geranylgeranylacetone (GGA) or by other compounds presently in development, may therefore be an interesting new approach for upstream therapy for AF, a strategy that aims to prevent AF whilst minimizing the ventricular proarrhythmic risks of traditional anti-arrhythmic agents.

Manganese Superoxide Dismutase as a Novel Oxidative Stress Biomarker for Predicting Paroxysmal Atrial Fibrillation.

BACKGROUND: There is accumulating evidence indicating that inflammation and oxidative stress are involved in the pathogenesis of atrial fibrillation (AF). The role of manganese superoxide dismutase (MnSOD) in the initiation and maintenance of AF has not yet been well characterized. The aim of our study is to investigate whether or not plasma MnSOD levels are associated with AF. METHODS: We enrolled a total of 130 consecutive patients with AF as the case group (paroxysmal AF: 87, persistent AF: 43) and 58 patients without a history of AF as the control group after screening. Baseline clinical characteristics, laboratory and echocardiographic parameters were collected. Plasma levels of nicotinamide-adenine dinucleotide phosphate oxidase 4 (NOX4) and MnSOD were measured by an enzyme-linked immunosorbent assay (ELISA) method. These data were compared between the different groups. The relationship between MnSOD and other parameters was assessed using Spearman correlation. Multivariable logistic regression analysis was performed to identify independent predictors of AF. The area under the curve (AUC) from receiver operating characteristics (ROC) analysis was constructed to explore the value of MnSOD in predicting the occurrence of AF. RESULTS: The levels of MnSOD were the highest in the paroxysmal AF group, followed by the persistent AF group, and the lowest in the controls. Meanwhile, the levels in the paroxysmal AF group were significantly higher than those in the controls [322.84 (165.46, 547.61) vs. 201.83 (129.53, 301.93), p = 0.002], but no significant difference was found between the paroxysmal AF group and persistent AF group, as well as the persistent AF group and the controls. Spearman correlation analysis indicated that there was a significantly negative correlation between MnSOD levels and LAD (r = -0.232, p = 0.008) and a positive correlation between MnSOD levels and RDW-CV (r = 0.214, p = 0.014) in the case group. Multivariate logistic regression analysis indicated that MnSOD levels [odds ratio (OR): 1.003, 95% confidence interval (CI): 1.001-1.005, p = 0.002] were an independent risk factor for paroxysmal AF, and the best cut-off value of MnSOD in predicting paroxysmal AF gained by ROC curve analysis was 311.49 ug/mL (sensitivity of 52.9%, specificity of 77.6%, AUC = 0.668). CONCLUSION: Oxidative stress underlies the pathogenesis of AF and may play a stronger role in paroxysmal AF than persistent AF. Our study showed an independent association between increased circulating plasma MnSOD levels and the occurrence of paroxysmal AF.

NADPH Oxidase Mediates Oxidative Stress and Ventricular Remodeling through SIRT3/FOXO3a Pathway in Diabetic Mice.

Oxidative stress and mitochondrial dysfunction are important mechanisms of ventricular remodeling, predisposed to the development of diabetic cardiomyopathy (DCM) in type 2 diabetes mellitus. In this study, we have successfully established a model of type 2 diabetes using a high-fat diet (HFD) in combination with streptozotocin (STZ). The mice were divided into three groups of six at random: control, diabetes, and diabetes with apocynin and the H9c2 cell line was used as an in vitro model for investigation. We examined the molecular mechanisms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial dysfunction and ventricular remodeling in the diabetic mouse model. Hyperglycemia-induced oxidative stress led to a reduced expression of sirtuin 3 (SIRT3), thereby promoting forkhead box class O 3a (FOXO3a) acetylation in ventricular tissue and H9c2 cells. Reactive oxygen species (ROS) overproduction promoted ventricular structural modeling and conduction defects. These alterations were mitigated by inhibiting NADPH oxidase with the pharmaceutical drug apocynin (APO). Apocynin improved SIRT3 and Mn-SOD expression in H9c2 cells transfected with SIRT3 siRNA. In our diabetic mouse model, apocynin improved myocardial mitochondrial function and ROS overproduction through the recovery of the SIRT3/FOXO3a pathway, thereby reducing ventricular remodeling and the incidence of DCM.

Circulating Vitamin D Concentrations and Risk of Atrial Fibrillation: A Mendelian Randomization Study Using Non-deficient Range Summary Statistics.

Background and Aims: Vitamin D deficiency is a common disorder and has been linked with atrial fibrillation (AF) in several observational studies, although the causal relationships remain unclear. We conducted a Mendelian randomization (MR) analysis to determine the causal association between serum 25-hydroxyvitamin D [25(OH)D] concentrations and AF. Methods and Results: The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from large genome-wide association meta-analyses conducted on serum 25(OH)D (N = 79,366) and AF (N = 1,030,836). Six SNPs related to serum 25(OH)D were used as instrumental variables. The association between 25(OH)D and AF was estimated using both the fixed-effect and random-effects inverse variance weighted (IVW) method. The MR analyses found no evidence to support a causal association between circulating 25(OH)D level and risk of AF using random-effects IVW (odds ratio per unit increase in log 25(OH)D = 1.003, 95% CI, 0.841-1.196; P = 0.976) or fixed-effect IVW method (OR = 1.003, 95% CI, 0.876-1.148; P = 0.968). Sensitivity analyses yielded similar results. No heterogeneity and directional pleiotropy were detected. Conclusion: Using summary statistics, this MR study suggests that genetically predicted circulating vitamin D concentrations, especially for a non-deficient range, were not causally associated with AF in the general population. Future studies using non-linear design and focusing on the vitamin D deficiency population are needed to further evaluate the causal effect of vitamin D concentrations on AF.

Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits.

AIMS: The mechanisms of atrial fibrillation (AF) in diabetes mellitus (DM) involve a complex interplay between increased oxidative stress, mitochondrial dysfunction and atrial remodeling. In this study, we examined the effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial oxidative stress and atrial remodeling in a rabbit model of diabetes mellitus (DM). MAIN METHODS: Healthy rabbits were selected and randomly divided into control, diabetic and apocynin administration group. Parameters of echocardiography, atrial electrophysiology, oxidative stress and mitochondrial function were compared between the different groups. KEY FINDINGS: Compared to the control group, the DM group showed higher activity of NADPH oxidase, increased oxidative stress, larger left atrial diameter, a reduction in atrial mean conduction velocity. These findings were associated with increased interstitial fibrosis of the atria and higher atrial fibrillation (AF) inducibility. Moreover, atrial ultrastructure and mitochondrial function such as the mitochondrial respiratory control rate (RCR) were impaired. NADPH oxidase inhibition using the pharmacological agent apocynin improved these changes. SIGNIFICANCE: NADPH oxidase activity plays an important role in mitochondrial oxidative stress, which is associated with AF inducibility by promoting adverse atrial remodeling. The NADPH oxidase inhibitor apocynin can prevent these pathological changes and may be a potential drug for AF treatment.