Construction and validation of a cuproptosis-related diagnostic gene signature for atrial fibrillation based on ensemble learning.

BACKGROUND: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. Nonetheless, the accurate diagnosis of this condition continues to pose a challenge when relying on conventional diagnostic techniques. Cell death is a key factor in the pathogenesis of AF. Existing investigations suggest that cuproptosis may also contribute to AF. This investigation aimed to identify a novel diagnostic gene signature associated with cuproptosis for AF using ensemble learning methods and discover the connection between AF and cuproptosis. RESULTS: Two genes connected to cuproptosis, including solute carrier family 31 member 1 (SLC31A1) and lipoic acid synthetase (LIAS), were selected by integration of random forests and eXtreme Gradient Boosting algorithms. Subsequently, a diagnostic model was constructed that includes the two genes for AF using the Light Gradient Boosting Machine (LightGBM) algorithm with good performance (the area under the curve value > 0.75). The microRNA-transcription factor-messenger RNA network revealed that homeobox A9 (HOXA9) and Tet methylcytosine dioxygenase 1 (TET1) could target SLC31A1 and LIAS in AF. Functional enrichment analysis indicated that cuproptosis might be connected to immunocyte activities. Immunocyte infiltration analysis using the CIBERSORT algorithm suggested a greater level of neutrophils in the AF group. According to the outcomes of Spearman's rank correlation analysis, there was a negative relation between SLC31A1 and resting dendritic cells and eosinophils. The study found a positive relationship between LIAS and eosinophils along with resting memory CD4+ T cells. Conversely, a negative correlation was detected between LIAS and CD8+ T cells and regulatory T cells. CONCLUSIONS: This study successfully constructed a cuproptosis-related diagnostic model for AF based on the LightGBM algorithm and validated its diagnostic efficacy. Cuproptosis may be regulated by HOXA9 and TET1 in AF. Cuproptosis might interact with infiltrating immunocytes in AF.

Left Bundle Branch Pacing: Current Knowledge and Future Prospects.

Cardiac pacing is an effective therapy for treating patients with bradycardia due to sinus node dysfunction or atrioventricular block. However, traditional right ventricular apical pacing (RVAP) causes electric and mechanical dyssynchrony, which is associated with increased risk for atrial arrhythmias and heart failure. Therefore, there is a need to develop a physiological pacing approach that activates the normal cardiac conduction and provides synchronized contraction of ventricles. Although His bundle pacing (HBP) has been widely used as a physiological pacing modality, it is limited by challenging implantation technique, unsatisfactory success rate in patients with wide QRS wave, high pacing capture threshold, and early battery depletion. Recently, the left bundle branch pacing (LBBP), defined as the capture of left bundle branch (LBB) via transventricular septal approach, has emerged as a newly physiological pacing modality. Results from early clinical studies have demonstrated LBBP's feasibility and safety, with rare complications and high success rate. Overall, this approach has been found to provide physiological pacing that guarantees electrical synchrony of the left ventricle with low pacing threshold. This was previously specifically characterized by narrow paced QRS duration, large R waves, fast synchronized left ventricular activation, and correction of left bundle branch block. Therefore, LBBP may be a potential alternative pacing modality for both RVAP and cardiac resynchronization therapy with HBP or biventricular pacing (BVP). However, the technique's widespread adaptation needs further validation to ascertain its safety and efficacy in randomized clinical trials. In this review, we discuss the current knowledge of LBBP.

The antagonistic effects and mechanisms of microRNA-26a action in hypertensive vascular remodelling.

BACKGROUND AND PURPOSE: Hypertensive vascular remodelling is responsible for end-organ damage and is the result of increased extracellular matrix accumulation and excessive vascular smooth muscle cell (VSMC) proliferation. MicroRNA-26a (miR-26a), a non-coding small RNA, is involved in several cardiovascular diseases. We aimed to validate the effect and mechanisms of miR-26a in hypertensive vascular remodelling. EXPERIMENTAL APPROACH: Male spontaneously hypertensive rats (SHRs) were injected intravenously with recombinant adeno-associated virus-miR-26a. Samples of thoracic aorta were examined histologically with H&E staining. In vitro, angiotensin II (AngII)-induced VSMCs cultured from thoracic aortae of female Sprague-Dawley rats, were transfected with miR-26a mimic or inhibitor. Western blots, qRT-PCR and immunohistological methods were used, along with chromatin-immunoprecipitation and luciferase reporter assays. Specific siRNAs were used to silence Smad production in VSMCs KEY RESULTS: Levels of miR-26a were lower in the thoracic aorta and plasma of SHRs than in WKY rats. Overexpression of miR-26a inhibited extracellular matrix deposition by targeting connective tissue growth factor (CTGF) and decreased VSMC proliferation by regulating the enhancer of zeste homologue 2 (EZH2)/p21 pathway both in vitro and in vivo. AngII-mediated Smad3 activation suppressed miR-26a expression, which in turn promoted Smad3 activation via targeted regulation of Smad4, leading to further down-regulation of miR-26a. CONCLUSION AND IMPLICATIONS: Our data show that AngII stimulated a Smads/miR-26a positive feedback loop, which further reduced expression of miR-26a, leading to collagen production and VSMC proliferation and consequently vascular remodelling. MiR-26a has an antagonistic effect on hypertensive vascular remodelling and can be a strategy for treating hypertensive vascular remodelling.

CXCL12/CXCR4 axis as a key mediator in atrial fibrillation via bioinformatics analysis and functional identification.

Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein-protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl2) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.

MicroRNA-26a Protects the Heart Against Hypertension-Induced Myocardial Fibrosis.

Background Hypertensive myocardial fibrosis (MF) is characterized by excessive deposition of extracellular matrix and cardiac fibroblast proliferation, which can lead to heart failure, malignant arrhythmia, and sudden death. In recent years, with the deepening of research, microRNAs have been found to have an important role in blood pressure control and maintaining normal ventricular structure and function. Methods and Results In this study, we first documented the downregulation of microRNA-26a (miR-26a) in the plasma and myocardium of spontaneously hypertensive rats; more importantly, miR-26a-deficient mice showed MF, whereas overexpression of miR-26a significantly prevented elevated blood pressure and inhibited MF in vivo and angiotensin II-induced fibrogenesis in cardiac fibroblasts by directly targeting connective tissue growth factor and Smad4. miR-26a inhibited cardiac fibroblast proliferation by the enhancer of zeste homolog 2/p21 pathway. Conclusions Our study identified a novel role for miR-26a in blood pressure control and hypertensive MF and provides a possible treatment strategy for miR-26a to alleviate and reverse hypertensive MF.