Quantitative analysis reveals influencing factors to facilitate successful anodal-ring capture in left bundle branch pacing.

AIMS: Left bundle branch pacing (LBBP) maintains left ventricular synchrony but induces right ventricular conduction delay (RVCD). Although anodal-ring capture (ARC) during bipolar LBBP improves RVCD, it is not achieved in all patients receiving LBBP. This study aimed to analyze the factors influencing ARC implementation. METHODS AND RESULTS: Patients receiving LBBP with intraoperative ARC testing were enrolled. Electrocardiographic parameters were measured, including stimulus-to-QRS duration (stim-QRSd), stimulus-to-left/right ventricular activation time (stim-LVAT/RVAT), and V6-V1 interpeak interval. The distribution of lead-tip sites was described as the corrected longitudinal and lateral distance (longit-/lat-dist). Relative angles of the LBBP lead were measured. Echocardiography in short-axis view was used to measure the intraseptal lead length. Intergroup comparisons, correlation analysis, and stepwise logistic regression were performed. In total, 105 patients were included, among which 65 (62%) patients achieved ARC at a pacing output ≤ 5.0 V/0.5 ms (average 3.1 V/0.5 ms). Anodal-ring capture further shortened the stim-QRSd by 13.1 ± 7.5 ms. Better unipolar-ring (cathodal) threshold and R-wave sensing in LBBP-ARC group indicated the critical role of ring-septum contact in ARC. Longer corrected longit-dist and shorter corrected lat-dist of lead-tip sites were positively correlated with higher success likelihood of ARC, likely due to the greater relative angle in which the lead enters the septum and consequently the longer intraseptal lead length and better ring-septum contact. CONCLUSION: This study elucidated the factors affecting the success likelihood of LBBP-ARC. These findings improve the understanding of LBBP-ARC, providing references for future research and clinical practice.

Efficacy and Safety of Leadless Pacemakers for Atrioventricular Synchronous Pacing: A Systematic Review and Meta-Analysis.

Leadless pacemakers with an atrioventricular synchrony algorithm represent a novel technology for patients qualified for VDD pacing. The current evidence of their performance is limited to several small-scale observational studies. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of this new technology. We systematically searched the PubMed, Embase, and Cochrane library databases from their inception to 12 September 2022. The primary efficacy outcome was atrioventricular synchrony after implantation, whereas the secondary efficacy outcome was the change in cardiac output represented by the left ventricular outflow tract velocity time integral (LVOT-VTI). The primary safety outcome was major complications related to the procedures and the algorithm. Means or mean differences with 95% confidence interval (95% CI) were combined using a random-effects model or a fixed-effects model. Finally, 8 published studies with 464 participants were included in the qualitative analysis. The pooled atrioventricular synchrony proportion was 78.9% (95% CI 71.9-86.0%), and a further meta-regression did not screen factors that contributed significantly to the heterogeneity. Additionally, a significant increase in atrioventricular synchrony of 11.3% (95% CI 7.0-15.7%, p < 0.01) was achieved in patients experiencing programming optimization. LVOT-VTI was significantly increased by 1.9 cm (95% CI 1.2-2.6, p < 0.01), compared with the VVI pacing mode. The overall incidence of complications was approximately 6.3%, with major complications related to the algorithm being extremely low. Overall, leadless pacemakers with atrioventricular synchronous pacing demonstrated favorable safety and efficacy. Future data on their long-term performance are required to facilitate their widespread adoption in clinical practice.

Additional left ventricular septal lead facilitates R-wave sensing of implantable cardioverter-defibrillator in arrhythmogenic right ventricular cardiomyopathy: a case report.

Background: Implantable cardioverter-defibrillator (ICD) implantation is a key therapeutic option in arrhythmogenic right ventricular cardiomyopathy (ARVC) to prevent sudden cardiac death due to ventricular tachycardia (VT) and fibrillation (VF). However, sub-optimized R-wave sensing due to myocardium loss interferes with VT/VF identification and appropriate therapy. We tried to implant a 3830 lead to the left ventricular septum (LVS) to facilitate ICD sensing in an ARVC patient. Case summary: A 68-year-old woman diagnosed with ARVC was scheduled to undergo ICD implantation. Initially, no sites with suitable R-wave amplitudes were found in the right ventricle (RV) to deploy the defibrillation lead (<3.0 mV). It was likely due to severe RV involvement, but the LVS myocardium was more preserved based on cardiac magnetic resonance imaging. Therefore, we implanted a 3830 lead into the deep area of the septum to facilitate R-wave sensing. During the procedure from the right to left septum, the R-wave amplitude significantly increased (2.6 to 4.3-7.1 mV). Left ventricular septum pacing was finally achieved with favourable R-wave sensing (9.9 mV 24 h post-operation). The 3830 lead was plugged into the IS-1 port, while the defibrillation lead was plugged into the DF-1 port. After a 4-month follow-up, the R-wave amplitude of the 3830 lead was 11.1 mV. Discussion: When the R-wave sensing is not acceptable for ICD implantation in ARVC patients, it is critical to assess myocardial conditions comprehensively. If the septal myocardium is preserved, implanting a 3830 lead to the deep or LVS is feasible to improve R-wave sensing.

Distance between the lead-implanted site and tricuspid valve annulus in patients with left bundle branch pacing: Effects on postoperative tricuspid regurgitation deterioration.

BACKGROUND: Left bundle branch pacing (LBBP) is an alternative strategy for His-bundle pacing (HBP); however, little is known about tricuspid regurgitation (TR) deterioration after LBBP implantation. OBJECTIVES: The purpose of this study was to characterize the incidence of post-LBBP TR deterioration and identify predicting factors, especially lead position parameters. METHODS: Patients who received LBBP were continuously enrolled from January 2018 to August 2020. The progression of TR and the anatomic position of LBBP were characterized by echocardiography. RESULTS: A total of 89 patients were enrolled and assigned to 2 subgroups based on the degree of TR before LBBP implantation: 58 (65.2%) with relatively normal tricuspid valve (TV) function (grade 0/1 subgroup: with none/trivial or mild TR) and 31 (34.8%) with more severe TR (grade 2/3 subgroup: with moderate or severe TR). At 19.0 ± 6.5 months of follow-up, 29 patients (32.6%) had TR deterioration, and 23 of them were in the grade 0/1 subgroup. In the grade 0/1 subgroup, patients with TR deterioration had a shorter distance between the lead-implanted site and TV (Lead-TA-dist) than those without TR (19.0 ± 7.6 vs 23.9 ± 5.4; P = .006). The receiver operating characteristic (ROC) curve (area under the curve 0.721; 95% confidence interval [CI] 0.575-0.867; P = .005) indicated the favorable efficacy of Lead-TA-dist for predicting TR deterioration after LBBP. Lead-TA-dist ≤16.1 mm was independently associated with TR deterioration after LBBP (hazard ratio 0.20; 95% CI 0.06-0.76; P = .017). CONCLUSION: TR was a common complication of LBBP implantation. In patients with none/trivial or mild TR, Lead-TA-dist ≤16.1 mm was an independent predictor of TR deterioration after LBBP implantation.

Association of glucagon-like peptide-1 receptor agonists with cardiac arrhythmias in patients with type 2 diabetes or obesity: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been highly recommended for glycemic control and weight reduction. However, evidence has accumulated that GLP-1 RAs treatment is related to an increase in heart rate, which could potentially induce cardiac arrhythmias. This study aims to investigate the association of GLP-1 RAs therapy with incident arrhythmias in diabetic and obese patients. METHODS: MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception up to May 25, 2022. Randomized controlled trials (RCTs) comparing GLP-1 RAs with placebo or active control for adults with type 2 diabetes or obesity were included. The outcomes of interest were prespecified as incident atrial fibrillation (AF), atrial flutter (AFL), ventricular arrhythmias (VAs), and sudden cardiac death (SCD). Mantel-Haenszel relative risk (MH-RR) with a corresponding 95% confidence interval (95% CI) was estimated using a fixed-effects model. RESULTS: A total of 56 RCTs involving 79,720 participants (44,028 GLP-1 RAs vs 35,692 control: mean age 57.3 years) were included from 7692 citations. GLP-1 RAs use overall did not significantly increase the risk of AF (RR 0.97, 95% CI 0.83-1.12), AFL (RR 0.83, 95% CI 0.59-1.17), VAs (RR 1.24, 95% CI 0.92-1.67), and SCD (RR 0.89, 95% CI 0.67-1.19), compared with controls. In further subgroup analyses, we observed an increasing trend toward incident AF with dulaglutide (RR 1.40, 95% CI 1.03-1.90) while an inverse trend with oral semaglutide (RR 0.43, 95% CI 0.21-0.87). Additionally, higher doses of GLP-1 RAs (RR 1.63, 95% CI 1.11-2.40) and higher baseline BMI (RR 1.60, 95% CI 1.04-2.48) might significantly increase the risk of VAs. No significant differences were identified in other subgroup analyses. CONCLUSIONS: GLP-1 RAs therapy was not associated with an overall higher risk of arrhythmias, demonstrating an assuring cardiovascular safety profile. Further studies are required to determine whether the potential antiarrhythmic or arrhythmogenic effect of GLP-1 RAs is drug-specific and varies from doses or baseline BMI. TRIAL REGISTRATION: PROSPERO Identifier: CRD42022339389.

Long-term follow-up results of patients with left bundle branch pacing and exploration for potential factors affecting cardiac function.

Background: Left bundle branch pacing (LBBP) is an alternative strategy for His bundle pacing (HBP). This study aimed to analyze the long-term performance of LBBP and the potential factors affecting long-term cardiac function. Methods: Patients with LBBP were continuously enrolled from January 2018 to August 2020. Pacing parameters, electrocardiogram (ECG), and echocardiography were collected. The anatomic position of LBBP leads was described by echocardiographic and fluoroscopic parameters. Results: A total of 91 patients with a median follow-up of 18 months were enrolled. Most patients maintained stable pacing parameters during follow-up. The intra-septal position of the 3830 lead also remained stable as the distance from the lead tip to the left surface of the ventricular septum was 0.4 (0, 1.4) mm. The overall level of left ventricular ejection fraction (LVEF) slightly increased. 59 patients had improved LVEF (∆LVEF > 0), while 28 patients had unchanged or reduced LVEF (∆LVEF ≤ 0). The declines of baseline LVEF, ∆ Paced QRSd, and corrected longitudinal distance (longit-dist) of lead-implanted site correlated with LVEF improvement, and these three factors had negative linear correlations with ∆LVEF. Patients with tricuspid valve regurgitation (TVR) deterioration had longer follow-up duration (20.5 vs. 15.0 months, p = 0.01) and shorter Lead-TVA-dist (18.6 vs. 21.6 mm, p = 0.04) than those without TVR deterioration. Conclusion: Patients with LBBP generally remained stable in pacing performance, anatomic lead positions, and cardiac function in long-term follow-up. Baseline LVEF, ∆ Paced QRSd, and corrected longit-dist might be associated with potential LVEF decrease, which required further confirmation.

The Landscape of Cell Death Processes with Associated Immunogenic and Fibrogenic Effects in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death. Cardiomyocyte death is an essential pathogenic mechanism in ACM, but the cell death landscape has never been elucidated. Our study aimed to address this problem based on RNA-sequencing (RNA-seq) data. Myocardial RNA-seq data from arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and normal controls were obtained from the Gene Expression Omnibus database (GSE107475, GSE107311, GSE107156, GSE107125). Signature gene sets of cell death processes, immune cells, and pathways were collected. Single-sample gene-set enrichment analysis calculated the enrichment scores for these signature gene sets. The RNA-seq data of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from an ACM patient were used for validation (GSE115621). Weighted gene coexpression network analysis (WGCNA) was applied to identify coexpression modules. Immunogenic cell death, apoptosis, necroptosis, and pyroptosis were significantly up-regulated in ARVC. Positive correlations of these four up-regulated cell death processes with immune cells and pathways were found within the ARVC myocardium. In the ARVC sample cluster with higher cell death levels, central memory CD4 T cell, memory B cell, type 1 T helper cell, mast cell, natural killer T cell, and plasmacytoid dendritic cell were more substantially infiltrated. Similarly, immune pathways were more up-regulated in this cluster. Positive linear correlations were found between cell death, immune responses, and myocardial fibrosis within the ARVC samples. Eventually, WGCNA identified a shared coexpression module related to these mechanisms. This study first demonstrated the landscape of cell death processes in the ACM (ARVC) myocardium and their positive correlations with immune responses and myocardial fibrosis. These mechanisms have potential interactions and jointly contribute to the pathogenesis of ACM.

Changes of repolarization parameters after left bundle branch area pacing and the association with echocardiographic response in heart failure patients.

Background: Left bundle branch area pacing (LBBAP) has become a safe and effective option for heart failure (HF) patients indicated for cardiac resynchronization therapy (CRT) and/or ventricular pacing, yet the response rate was only 70%. Repolarization parameters were demonstrated to be associated with cardiac mechanics and systolic function. This study aimed to investigate the effects of LBBAP on repolarization parameters and the potential association between those parameters and echocardiographic response. Methods and results: A total of 59 HF patients undergoing successful LBBAP were consecutively included. QTc, Tpeak-Tend (TpTe), and TpTe/QTc were measured before and after the implantation. The results turned out that the dispersion of ventricular repolarization (DVR) improved after LBBAP among the total population. Although trends of repolarization parameters varied according to different QRS configurations at baseline, the post-implant parameters showed no significant difference between groups. The association between repolarization parameters and LBBAP response was then evaluated among patients with wide QRS. Multivariate analysis demonstrated that post-implant TpTe was the independent predictor of LBBAP response (p < 0.05). Receiver operating characteristic analysis indicated an area under the curve of 0.77 (95% CI, 0.60-0.93) with a cutoff value of 81.2 ms (p < 0.01). Patients with post-implant TpTe<81.2 ms had a significantly higher rate of echocardiographic response (93.3 vs. 44.4%, p < 0.01). Further subgroup analysis indicated that the predictive value of post-implant TpTe for LBBAP response was more significant in non-left bundle branch block (LBBB) patients than in LBBB patients. Conclusion: LBBAP improved DVR significantly in HF patients. Post-implant TpTe was associated with the echocardiographic response after LBBAP among patients with wide QRS, especially for non-LBBB patients.

Dominant Myocardial Fibrosis and Complex Immune Microenvironment Jointly Shape the Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable life-threatening myocardial disease characterized by ventricular arrhythmias and sudden cardiac death. Few studies used RNA-sequencing (RNA-seq) technology to analyze gene expression profiles, hub genes, dominant pathogenic processes, immune microenvironment in ARVC. This study aimed to explore these questions via integrated bioinformatics analysis. Methods: RNA-sequencing datasets of GSE107475, GSE107311, GSE107156, and GSE107125 were obtained from the Gene Expression Omnibus database, including right and left ventricular myocardium from ARVC patients and normal controls. Weighted gene co-expression network analysis identified the ARVC hub modules and genes. Functional enrichment and protein-protein interaction analysis were performed by Metascape and STRING. Single-sample gene-set enrichment analysis (ssGSEA) was applied to assess immune cell infiltration. Transcription regulator (TF) analysis was performed by TRRUST. Results: Three ARVC hub modules with 25 hub genes were identified. Functional enrichment analysis of the hub genes indicated that myocardial fibrosis was the dominant pathogenic process. Higher myocardial fibrosis activity existed in ARVC than in normal controls. A complex immune microenvironment was discovered that type 2 T helper cell, type 1 T helper cell, regulatory T cell, plasmacytoid dendritic cell, neutrophil, mast cell, central memory CD4 T cell, macrophage, CD56dim natural killer cell, myeloid-derived suppressor cell, memory B cell, natural killer T cell, and activated CD8 T cell were highly infiltrated in ARVC myocardium. The immune-related hub module was enriched in immune processes and inflammatory disease pathways, with hub genes including CD74, HLA-DRA, ITGAM, CTSS, CYBB, and IRF8. A positive linear correlation existed between immune cell infiltration and fibrosis activity in ARVC. NFKB1 and RELA were the shared TFs of ARVC hub genes and immune-related hub module genes, indicating the critical role of NFκB signaling in both mechanisms. Finally, the potential lncRNA-miRNA-mRNA interaction network for ARVC hub genes was constructed. Conclusion: Myocardial fibrosis is the dominant pathogenic process in end-stage ARVC patients. A complex immune microenvironment exists in the diseased myocardium of ARVC, in which T cell subsets are the primary category. A tight relationship exists between myocardial fibrosis activity and immune cell infiltration. NFκB signaling pathway possibly contributes to both mechanisms.

The therapeutic effects of upgrade to cardiac resynchronization therapy in pacing-induced cardiomyopathy or chronic right ventricular pacing patients: a meta-analysis.

Pacing-induced cardiomyopathy (PICM) or heart failure accompanied with chronic right ventricular pacing (CRVP-HF) has no established treatments. We aimed to carry out a meta-analysis of published studies about the therapeutic effects of the upgrade to cardiac resynchronization therapy (CRT) in patients of PICM/CRVP-HF. The PUBMED, EMBASE, MEDLINE, OVID databases, and Cochrane Library were systemically searched for relevant publications. Data about the improvements of left ventricular ejection fraction (LVEF), NYHA functional class (NYHA-FC), and the CRT response rate was extracted and synthesized. Mean difference (MD), odds ratio, and standard mean difference (SMD) with 95% confidence interval (CI) were calculated as the effect size by both fixed and random effect models. We included sixteen studies (four about PICM and twelve about CRVP-HF). The total sample size of PICM/CRVP-HF patients was 924. Upgrade to CRT improved the LVEF by 10.87% (95%CI, 8.90 to 12.84%) and reduce the NYHA-FC by around one class (MD, -1.25; 95%CI, -1.43 to -1.06) in PICM/CRVP-HF patients overall. Upgrade to CRT seemed to improve LVEF no less than de-novo CRT (SMD 0.24; 95%CI 0.05 to 0.43; P < 0.05). This meta-analysis suggested that upgrade CRT could improve the cardiac function in PICM/CRVP-HF patients. This strategy may be considered in these patients but require more evidence about the efficacy and procedure-related complications from prospective studies or randomized controlled trials.

Quantitative distance and electrocardiographic parameters for lead-implanted site selection to enhance the success likelihood of left bundle branch pacing.

BACKGROUND: Left bundle branch pacing (LBBP) is a novel near-physiological pacing method that still lacks quantitative criteria to guide the selection of lead-implanted sites to enhance the success likelihood of lead deployments. This study aimed to quantitatively analyze the relationships of LBBP success likelihood to the distribution of lead-implanted sites and the lead-localization-pacing electrocardiographic (ECG) features. METHODS: All the lead-implanted sites in patients with finally successful LBBP were enrolled for analysis, including successful and failed sites. A novel coordinate system was invented to describe the sites' distribution as longitudinal distance (longit-dist) and lateral distance (lat-dist). Corrected distance parameters were generated to eliminate the cardiac dimension variations. The lead-localization-pacing ECG parameters were also collected, such as paced QRS duration (locat-QRSd), left ventricular activation time (locat-LVAT), LVAT/QRSd ratio (locat-LVAT/QRSd), and QRS directions. RESULTS: A total of 94 patients with 105 successful sites and 93 failed sites were enrolled. Longit-dist and corrected longit-dist of successful sites were significantly longer, while locat-QRSd and locat-LVAT were shorter and locat-LVAT/QRSd was lower than failed sites. There was a positive dose-response relationship between LBBP success likelihood and corrected longit-dist with a cut-off of 26.95 mm, whereas there were negative dose-response relationships of LBBP success likelihood to locat-QRSd, locat-LVAT, and locat-LVAT/QRSd with the cut-offs of 142 ms, 92 ms, and 64.7%, respectively. Downward QRS direction in II/III ECG leads was also associated with successful LBBP. CONCLUSION: Longit-dist, locat-QRSd, locat-LVAT, and locat-LVAT/QRSd were quantitative parameters to guide the selection of lead-implanted sites during LBBP implantation. Quantitative distance and electrocardiographic parameters for lead-implanted site selection to enhance the success likelihood of left bundle branch pacing. LBBP, left bundle branch pacing; Longit-dist, longitudinal distance; CL-apex-dist, distance from contraction line to apex; LBBB, left bundle branch block; IVCD, intraventricular conduction delay; Locat-QRSd, lead-localization-pacing QRS duration; Locat-LVAT, lead-localization-pacing left ventricular activation time; Locat-LVAT/QRSd, lead-localization-pacing LVAT/QRSd ratio.

Relationship of paced left bundle branch pacing morphology with anatomic location and physiological outcomes.

BACKGROUND: Left bundle branch pacing (LBBP) is an emerging physiological pacing modality. However, little is known about pacing at different locations on the left bundle branch (LBB). OBJECTIVE: The purpose of this study was to explore pacing and physiological characteristics associated with different LBBP locations. METHODS: The study included 68 consecutive patients with normal unpaced QRS duration and successful LBBP implantation. Patients were divided into 3 groups according to the paced QRS complex as left bundle branch trunk pacing (LBTP), left posterior fascicular pacing (LPFP), or left anterior fascicular pacing (LAFP). Electrocardiographic (ECG) characteristics, pacing parameters, and fluoroscopic localization were collected and analyzed. RESULTS: There were 17 (25.0%), 35 (51.5%), and 16 (23.5%) patients in the LBTP, LPFP, and LAFP groups, respectively. All subgroups had relatively narrow paced QRS complex (128.6 ± 9.1 ms vs 133.7 ± 11.2 ms vs 134.8 ± 9.6 ms; P = .170), fast left ventricular activation (70.4 ± 9.0 ms vs 70.6 ± 10.2 ms vs 71.0 ± 9.0 ms; P = .986), as well as low and stable pacing thresholds. Delayed right ventricular activation and interventricular dyssynchrony were similar between groups. Fluoroscopic imaging indicated that the lead tip was located most commonly in the basal-middle region of the septum (67.7%), and this was independent of paced QRS morphology group (88.2% vs 57.1% vs 68.8%; P = .106). CONCLUSION: Pacing at different sites of the LBB resulted in similar intraventricular and interventricular electrical synchrony in patients with an intact conduction system. Fluoroscopic imaging alone could not predict specific LBBP paced ECG morphology.

Association Between High FSH, Low Progesterone, and Idiopathic Pulmonary Arterial Hypertension in Women of Reproductive Age.

BACKGROUND: While sex differences characterize susceptibility and severity of idiopathic pulmonary arterial hypertension (IPAH), our understanding of the relationship between levels of gonadotropins and sex hormones in fertile women and the disease is limited. We aimed to investigate whether gonadotropin and sex hormone levels in women of reproductive age were associated with risk and mortality of IPAH. METHODS: We did a matched case-control study. Cases were reproductive female patients with idiopathic pulmonary arterial hypertension admitted in Shanghai Pulmonary Hospital (Tongji University School of Medicine, Shanghai, China) during 2008-2014. Healthy controls were matched on age and body mass index. We also did a prospective cohort study to assess the effects of hormone levels on mortality in IPAH fertile female patients. RESULTS: One hundred sixty-four cases and 133 controls were included. After adjustment for age and body mass index, the odds ratios of having IPAH for follicle-stimulating hormone, testosterone, and progesterone as expressed on natural log scale were 1.51 (95% confidence interval: 1.06, 2.16), 0.42 (0.31-0.57), and 0.52 (0.43-0.63), respectively. In the cohort study with a median follow-up of 77 months, the hazard ratios for dying after adjustment for baseline characteristics and treatments among IPAH patients were 2.01 (95% confidence interval: 1.22-3.30) and 0.78 (95% confidence interval: 0.62-0.98) for follicle-stimulating hormone and progesterone in natural log scale, respectively. CONCLUSIONS: In reproductive women with IPAH, high follicle-stimulating hormone and low progesterone tended to be associated with high risk of IPAH and mortality among patients.