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Background: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. Methods: We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. Results: We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction–induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Conclusions: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

Background Remote magnetic navigation (RMN)‐guided ablation has become an inspiring method of catheter ablation for tachyarrhythmias. Hypothesis Data from a large‐scale single center may provide further insight into the safety of and the learning curve for RMN‐guided ablation. Methods A total of 1003 catheter ablation procedures using RMN for conditions including supraventricular ventricular tachycardia, atrial tachyarrhythmias, and premature ventricular contraction/ventricular tachycardia (PVC/VT) were retrospectively analyzed from an ablation registry. Procedural outcomes, including procedure time, mapping time, X‐ray time, and RF time, were assessed. The complications were classified into two categories: major and minor. A subanalysis was used to illustrate the learning curve of RMN‐guided ablation by assessing procedure time and total X‐ray time of 502 atrial fibrillation (AF) ablation procedures. Results Among these procedures, 556 (55.4%) were AF and 290 (28.9%) were PVC/VT. Electrical pulmonary vein isolation was achieved in 99.0% of AF procedures, and acute success reached 90.3% in PVC/VT procedures. The overall complication rate was 0.5%. In the subanalysis of AF procedures, the overall procedure time and X‐ray time of procedures were short (125.9 ± 54.6 and 5.3 ± 3.9 minutes, respectively) and proceeded to decrease from the initial 30 procedures to about 300 procedures, where the learning curve reached plateau, demonstrating maximum procedure efficiency. Conclusions RMN‐guided ablation is safe, as verified by very low overall complication rate and reduced X‐ray time. In our study, even the first AF procedures had a relatively low procedure time and total X‐ray time, and procedure efficiency improved during the learning curve.

The aim of this review was to evaluate the efficacy and safety between remote magnetic navigation (RMN) and manual control navigation (MCN) for atrial fibrillation (AF) ablation.We searched the PubMed, EMBASE and Cochrane library databases using the key words AF, ablation and magnetic navigation.Eighteen studies were identified in this analysis including 4046 patients comparing RMN and MCN in AF ablation, which were all non-randomized controlled studies. No significant difference of AF recurrence rate (40% vs. 38%, OR 1.00, 95% CI 0.82-1.22, p = 0. 97) and acute success rate in achieving pulmonary vein isolation (91% vs. 93%, OR 0.44, 95% CI 0.16-1.17, p = 0.10) was found between RMN and MCN. However, compared with MCN, RMN was associated with significantly lower complication rate (2% vs. 5%, OR 0.44, 95% CI 0.28-0.69, p = 0. 0003) and shorter fluoroscopy time (MD -9.71 min, 95% CI -15.80 to -3.63, p = 0.002). Procedure time (MD 47.05 min, 95% CI 27.5-66.58, p 0.00001) and ablation time (MD 15.90 min, 95% CI 9.62-22.18, p 0.00001) of RMN guided AF ablation were significantly longer than those of MCN.The results of this study suggest that RMN is as effective as MCN in achieving pulmonary vein isolation and freedom from AF recurrence, and has superior safety with less complications and shorter fluoroscopy time.

Background The development of atrial fibrillation (AF) following valvular heart disease (VHD) remains a common disease and is associated with substantial adverse complications. However, valid molecular diagnostic and therapeutic tools for post-VHD AF have not been fully established. This study was conducted to discover the molecular mechanisms and immune microenvironment underlying AF following VHD. Methods Gene expression profiles of the GSE41177 dataset were assessed to construct a protein–protein interaction network, and then, autophagy-related hub genes were identified. In addition, to determine the functions of immune cell infiltration in valvular AF, we used the CIBERSORT algorithm to estimate the composition of 22 immune cell types in valvular heart disease. Finally, correlation analysis was carried out to identify the relationship between differentially expressed autophagy-related genes (DEARGs) and significant immune cell subpopulations to reveal potential regulatory pathways. Results A total of 153 DEARGs were identified in AF-VHD patients compared with controlled donors. Moreover, we screened the top ten hub nodes with the highest degrees through a network analysis. The ten hub nodes were considered hub genes related to AF genesis and progression. Then, we revealed six significant immune cell subpopulations through the CIBERSORT algorithm. Finally, correlation analysis was performed, and six DEARGs (BECN1, GAPDH, ATG7, MAPK3, BCL2L1, and MYC) and three immune cell subpopulations (T cells CD4 memory resting, T cells follicular helper, and neutrophils) were identified as the most significant potential regulators. Conclusion The DEARGs and immune cells identified in our study may be critical in AF development following VHD and provide potential predictive markers and therapeutic targets for determining a treatment strategy for AF patients.

Additional file 1. Supplemental methods.

The optimized strategy to further increase the success rate of ablation for ventricular arrhythmias (VAs) from the right ventricular outflow tract (RVOT) is challenging. Recent studies have shown that the pulmonary sinus cusp (PSC) region may be the origin of certain RVOT VAs. We evaluated the efficacy of preferential ablation below the pulmonary valve (PV) and alternated radiofrequency delivery in the PSC using remote magnetic navigation (RMN). Sixty-five (65) consecutive patients experiencing VAs with RVOT-like appearance were included in this study. Mapping and ablation were preferentially performed below the PV. Ablation in the PSC would only be attempted when intensified ablation below the PV could not eliminate VAs. Finally, if ablation in the RVOT region failed, the aortic sinus cusp (ASC) would be mapped. Sixty-one (61) of 65 (93.8%) patients achieved procedural success. Except 7 cases of which the VAs were ablated in the ASC, the rest 54 VAs were thought to be originate from the RVOT region. Fifty (50) of 54 VAs were successfully ablated below the PV, and in the presence of a local special signal in the bipolar electrogram a more aggressive ablation was required. Subsequent ablation in the PSC with assistance of the RMN system achieved success in the remaining 4 patients. No complications occurred in this study. Our strategy of using RMN-guided ablation below the PV for VAs of RVOT origin was proved to be effective. PSC mapping and ablation using a magnetic catheter may provide the optimal strategy for treating these types of arrhythmias.

Navitoclax, which is a type of senolytic drug, selectively eliminates senescent cells. This study aimed to evaluate the therapeutic potential of navitoclax in treatment of angiotensin II (Ang II)-induced heart failure in mice. Navitoclax or vehicle was administrated in mice with Ang II-induced heart failure. Cardiac function and electrophysiology were assessed before and after administration of navitoclax. Cardiac remodeling, including morphological changes, fibrosis, and inflammatory responses, was analyzed in myocardial tissue. Cellular effects of navitoclax were validated in isolated primary cardiomyocytes and cardiac fibroblasts in vitro. Echocardiography of mice showed that navitoclax improved cardiac dysfunction by improving the left ventricular ejection fraction (vehicle: 45.88 ± 2.19%; navitoclax: 54.70 ± 1.65%, P < 0.01). In cardiac electrophysiological testing, navitoclax increased conduction velocity (vehicle: 1.37 ± 0.05 mm/ms; navitoclax: 1.69 ± 0.08 mm/ms, P < 0.05) and decreased susceptibility to ventricular tachyarrhythmia induced by programmed electrical stimulation. Histopathological staining, immunofluorescence, and western blotting examinations showed that navitoclax ameliorated Ang II-induced cardiac fibrosis, hypertrophy, and the inflammatory response. Moreover, navitoclax eliminated senescent cells by inducing apoptosis. Therefore, navitoclax improved cardiac function and electrophysiological characteristics through decreasing cardiac fibrosis, hypertrophy, and inflammation in mice with heart failure. Pharmacological clearance of senescent cells may be a potential therapeutic approach in heart failure with reduced ejection fraction.

Introduction Catheter ablation of frequent para-Hisian premature ventricular contractions (PH-PVCs) is considered to be challenging. The purpose of this study was to evaluate the strategy, potential technical advantages, and clinical outcomes of remote magnetic navigation (RMN) in the ablation of PH-PVCs. Methods Fifteen consecutive patients with PH-PVCs were included in this study. Electrical mapping was initially performed in the right ventricular septum by manipulating the RMN catheter with a "U-curve." In the case of no optimal ablation site or ablation failure, the ablation catheter was directed to the left ventricular (LV) septum through a transseptal approach for further mapping and ablation by manipulating the RMN catheter with a "reverse S-curve." Results Nine of 15 patients were submitted to ablation on the right side. However, ablation success was only achieved in only three (33%) cases. Of the other 12 patients, 11 underwent LV mapping and ablation. In this subset, 9 of 11 (82%) PH-PVCs were totally eliminated on the left side. Overall, RMN-guided mapping and ablation successfully eliminated 12 (80%) of 15 idiopathic PH-PVCs. During follow-up, the reoccurrence of PVCs was reported in 1 (8%) of 12 patients. No atrioventricular block was observed during or after the procedure. Conclusion RMN-guided catheter ablation for PH-PVCs is effective and safe in unselected patients. Due to the excellent reachability and contact with special morphologies of the RMN catheter on both sides of the ventricular septum, RMN can be considered an effective approach for frequent PH-PVCs.