RARE DISEASE
Familial sick sinus syndrome
Familial sick sinus syndrome
Familial sick sinus syndrome
Drug discovery
817
papers
On emerging therapies
Overview
Familial Sick Sinus Syndrome (SSS) is a rare inherited cardiac conduction disorder characterized by impaired sinoatrial node function, leading to bradycardia, atrial arrhythmias, syncope, or fatigue. It is linked to mutations in SCN5A, HCN4, or MYH6 genes, altering ion channel function or myocardial contractility. Inheritance patterns vary (autosomal dominant/recessive). Diagnosis requires ECG documentation of rhythm abnormalities alongside symptoms.
Therapies
Pacemaker implantation: First-line for symptomatic patients (50% of cases require dual-chamber devices) [3][8][17].
Anticoagulation: For atrial fibrillation-related thromboembolic risk (warfarin/direct oral anticoagulants) [3][8].
Gene-specific management: Avoid sodium channel blockers in SCN5A mutations; monitor for overlapping channelopathies (e.g., Brugada syndrome) [19][16].
Categories: rare cardiac diseases, rare genetic diseases
Research Papers
817 drug discovery papers about Familial sick sinus syndrome. Recent publications:
817 drug discovery papers about Familial sick sinus syndrome. Recent publications:
categories:
Small molecules
cell therapies
2026-09-23 | The role of atrioventricular delay in left bundle branch stimulation: when diastole is more important than systole
We present a clinical case of an 86yearold patient with initially preserved left ventricular ejection fraction, left bundle branch block, and sick sinus syndrome, who underwent implantation of a dualchamber pacemaker with selective left bundle branch pacing. With a programmed short atrioventricular delay (100/120 ms) and a high percentage of ventricular pacing, progression of chronic heart failure, a decrease in left ventricular ejection fraction, and worsening exercise tolerance were observed, without signs of myocardial ischemia, significant tachyarrhythmia, or loss of conduction system capture. Using echocardiographic parameters according to Ritter’s method, an optimal atrioventricular interval was selected, which resulted in restoration of atrioventricular synchrony and an increase in left ventricular ejection fraction.
2026-06-29 | First dual-chamber leadless pacemaker implantation at Meitra United Heart Centre, Kasaragod: a regional milestone in an octogenarian with sick sinus syndrome: a case report
Leadless pacemaker technology has advanced to enable dual-chamber atrioventricular synchronous pacing through implant-to-implant communication between two independent leadless devices. We report the first AVEIR dual-chamber leadless pacemaker implantation performed at Meitra United Heart Centre (MUHC), marking a regional milestone for Kasaragod, Kannur, Coastal Karnataka, and Goa. An 86-year-old woman presented with sick sinus syndrome complicated by tachy-brady syndrome and presyncopal episodes. She underwent successful implantation of a dual-chamber leadless pacemaker via femoral venous access under general anesthesia using the Innvolution Pinnacle Agile Cath Lab at MUHC. Optimal electrical parameters were achieved, with a right ventricular threshold of 0.5 V at 0.4 ms and impedance of 750 Ω, and a right atrial threshold of 1.0 V at 0.4 ms and impedance of 310 Ω. Device-to-device communication was 100%. Postoperatively, the patient developed left femoral vein thrombosis, which was managed with anticoagulation therapy, and she was discharged in stable condition. This case demonstrates that dual-chamber leadless pacing is feasible in an octogenarian with sick sinus syndrome and may serve as an alternative to conventional transvenous pacing systems, while emphasizing the need to consider vascular access complications such as femoral vein thrombosis during patient selection.
2026-02-24 | Upgrading expandable leadless pacemakers from single- to dual-chamber.
The aim of this analysis was to evaluate the upgradeability of a single-chamber leadless pacemaker (LP) to a dual-chamber system in patients indicated for a dual-chamber pacemaker. A prospective, multicentre study evaluated the safety and performance of a dual-chamber LP. The study included patients with a prior ventricular LP to evaluate its upgradeability. Patients had an attempted atrial LP implant, and if successfully implanted, the LPs were paired to a dual-chamber pacing mode to evaluate upgrade success. Patients were followed for 12 months from the attempted atrial LP implantation. Among 35 patients with an attempted upgrade (62.9% male, average age 70 years), the most common primary indication was sinus node dysfunction (57.1%). Out of 35 patients, 91.4% had successful upgrades. The mean atrial device electrical measurements stabilized within 1 month from the procedure and remained stable through 12 months (capture threshold at 0.4 ms 0.8 ± 0.6 V, sense amplitude 4.5 ± 2.7 mV at 12 months). A total of five (14.3%) patients experienced seven complications, all of which were procedure-related. There were no device or procedure-related deaths. The total estimated battery longevity (accounting for time since implant) evaluated at 12 months was 11.3 ± 4.2 and 5.7 ± 2.6 years for the ventricular and atrial LPs, respectively. One patient required an atrial LP revision 10 months after implantation. The LP was retrieved and replaced. These data confirm the feasibility, safety, and long-term effectiveness of adding an atrial LP in patients with a pre-existing ventricular LP to achieve dual-chamber leadless pacing.
2026-01-01 | Evaluation of the Feasibility and Safety of Left Ventricular Pacing Using Left Bundle Branch Area Pacing (LBBAP) Without Backup Right Ventricular Pacing Lead
All articles of this category (opens in new window) Background: This study aims to evaluate the feasibility and safety of sole left ventricular pacing using left bundle branch area pacing (LBBAP) without a backup right ventricular lead. Methods: Patients who were over 18 years old and received a pacemaker with left bundle branch area pacing (LBBAP) with no additional right ventricular lead implantation from June 2023 through October 2024 in a single center were included. Patients with incomplete documentation and those who failed to provide informed consent were excluded. Preoperative, intraoperative, and postoperative data were retrospectively collected. A prospective follow-up with determination of changes in Rheobase, lead impedance, and sensing (postoperatively, at 6 weeks, and at 6 months) was documented, as well as lead dislocation or pacemaker-related complications. NT-pro-BNP values were evaluated 6 months after implantation. Results: A total of 42 patients were included, with a mean age of 77 ± 10 years, 68% males, 83% in sinus rhythm, mean EF of 54 ± 7%. The main indication was a third-degree AV-Block (34%), bradycardia-tachycardia syndrome (24%) sick sinus syndrome (24%). The mean operative time was 60 ± 10 minutes. The mean radiation dose was 1,103 ± 561 (cGy) cm 2 The LBBAP QRS time was 112 ms. Three patients suffered a postoperative hematoma and were treated conservatively. Two patients suffered a dislocation of the LBBA lead, and they were repositioned. During follow-up, one patient died of pneumonia. The follow-up data were complete for the remaining 41 patients. There were no late dislocations or pacemaker-related complications. The Rheobase significantly increased from a mean of 0.55 mV after implantation to 0.82 mV after 6 weeks ( p < 0.001) and did not change significantly after 6 months (0.82 vs. 0.69 mV, respectively, p > 0.999). The mean electrode impedance improved significantly after 6 weeks (391 vs. 469 Ohm perioperatively, p = 0.02) and did not change significantly after 6 months. The sensing did not change significantly over time (11.8 vs. 12.3 vs. 12.2 mV; p = 0.085). The NT-proBNP did not change significantly over 6 months (1,422 vs. 2,001 pg/mL ; p = 0.764). Conclusion: LBBAP is a safe and stable approach that provides a more physiological pacing. The pacing electrodes are stable, their parameters stay stable over time, and a dislocation is only seen perioperatively. A backup right ventricular lead may not be needed with increased experience, yet longer perioperative monitoring might be warranted to exclude perioperative dislocation. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-12-10 | Platelet-bioengineered hiPSC-sEVs achieve targeted repair of fibrotic sinoatrial node in preclinical SND models.
Sinus node dysfunction, a prevalent arrhythmia in aging populations, is characterized by fibrosis and loss of pacemaker activity, necessitating pacemaker implantation. Current therapies fail to reverse the underlying pathology. Small extracellular vesicles derived from human induced pluripotent stem cells possess regenerative potential but lack targeted delivery. Here, we engineer platelet membrane-fused vesicles that synergistically combine collagen targeting for ischemic injury homing with immune evasion. In a rat model of sinus node dysfunction, these modified vesicles exhibit 3.1-fold higher accumulation in the sinoatrial node compared to unmodified vesicles, resulting in a 63% reduction in fibrosis and significant restoration of heart rate and intrinsic pacemaker function. The vesicles mitigate fibroblast activation and protect cardiomyocytes from oxidative stress. This study establishes a targeted, cell-free nanotherapeutic platform for resolving fibrosis and electrophysiological dysfunction in sinus node disease.
small molecules
2026-08-13 | Expression Defects of SCN5A Common Polymorphisms S524Y and H558R in the Q1077 Splice Variant Can Be Rescued by Mexiletine.
The cardiac sodium channel NaV1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of NaV1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine "rescued" expression deficiencies in the Brugada syndrome. Cells expressing S524Y/Q1077 and H558R/Q1077 were incubated for 48 h with or without mexiletine (500 μM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y/Q1077 and H558R/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms.
2026-08-12 | Efficacy and safety of Lingbao Huxin Dan in the treatment of sick sinus syndrome: a randomized, single-blind, placebo-controlled, crossover trial
Background Permanent pacemaker implantation is the standard treatment for symptomatic sick sinus syndrome (SSS), but it does not reverse the underlying sinus node dysfunction. Lingbao Huxin Dan (LBHXD) may benefit patients with bradyarrhythmia. However, robust clinical evidence regarding its efficacy and safety in patients with SSS, particularly those with pacemakers, is lacking. Methods A randomized, crossover trial was conducted. Thirty patients with SSS and implanted DDD pacemakers were enrolled and randomly assigned to one of two treatment sequences: LBHXD followed by placebo, or placebo followed by LBHXD. Each treatment period lasted 4 weeks, separated by a 2-week washout interval. Results 25 patients completed the trial. Following propensity score matching, 17 patients were included in the final analysis. Compared to the placebo phase, LBHXD administration resulted in a significantly greater reduction in AP% (38.99% ± 20.67% vs. 48.03% ± 21.95%, P < 0.01). LBHXD also significantly increased several HRV indices, including SDNN, SDANN, rMSSD, and SDNN index (all P < 0.05), and elevated the mean and maximum HR ( P < 0.05). No significant changes were observed in ventricular pacing percentage, left atrial diameter, or left ventricular ejection fraction. Conclusion Adjunctive therapy with Lingbao Huxin Dan can effectively reduce atrial pacing dependency, improve heart rate variability, and increase heart rate in patients with SSS and pacemakers, demonstrating a favorable safety profile. These findings suggest that LBHXD may enhance intrinsic sinoatrial node function and autonomic regulation, supporting its potential role as a complementary therapy in an integrative medicine approach to managing SSS. Clinical Trial Registration https://www.chictr.org.cn/showproj.html?proj=187346 , Chinese Clinical Trial Registry ChiCTR2300067497.
2026-08-04 | The Effect of Psychotropic Agents on Sick Sinus Syndrome: A Case Report
Sick sinus syndrome (SSS) presents significant challenges in psychiatric medication management because of the potential for worsening cardiac conduction and interactions with antiarrhythmic therapy. A 35-year-old woman with generalized anxiety disorder (GAD) and insomnia was treated with bupropion, hydroxyzine, melatonin, and intermittent quetiapine, alongside comorbid SSS and supraventricular tachycardia managed post-ablation with metoprolol. A review of her regimen identified several cardiac safety concerns: quetiapine’s potential interference with flecainide, hydroxyzine-associated QT prolongation, and bupropion’s CYP2D6 inhibition that could increase flecainide levels. Management prioritized minimizing arrhythmogenic risk by discontinuing quetiapine, restricting hydroxyzine to low doses, and continuing melatonin, supplemented by stress testing and reassessment of psychotropic options. This case highlights the importance of careful psychotropic selection in patients with SSS, favoring lower-risk agents, such as mirtazapine, which is one of the safest among several possible alternatives, while maintaining close ECG monitoring and coordinated cardiology and psychiatry collaboration to reduce drug-drug interactions and optimize safety.
2026-07-15 | Cardiac Pacemaker Cells Harness Stochastic Resonance to Avoid Sinus Arrest.
The sinoatrial node (SAN) is the primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials exiting the SAN emerge from heterogeneous signals, including subthreshold signals in nonfiring (dormant) cells. This raises a new question in cardiac biology: how do these signals contribute to heartbeat generation? Here, we tested the hypothesis that pacemaker cells harness stochastic resonance to ensure fail-safe operation, especially at low rates bordering on sinus arrest. Membrane potential and Ca signals were measured using perforated-patch recordings in rabbit SAN cells exposed to sine-wave or white-noise currents. In addition, we imaged Ca signals in intact mouse SAN tissue and performed multiscale model simulations at the subcellular, cellular, and tissue levels. In addition to synchronized Ca transients, SAN tissue exhibited heterogeneous local Ca signals with different kinetics. Noise currents, mimicking the heterogeneous natural cellular environment, restored action potential firing in dormant cells and substantially improved the rate and rhythm of cells firing infrequently and irregularly. Performance followed a bell-shaped curve, peaking and then declining, demonstrating a hallmark of stochastic resonance. Rhythmic action potential generation in response to sine-wave currents of different frequencies defined a resonance spectrum in SAN cells, reflecting their ability to respond via stochastic resonance to specific frequency components embedded in noise. Cholinergic stimulation shifted the resonance spectrum and responses to noise toward lower frequencies across all amplitudes tested, rendering cells unresponsive to higher-frequency signals while enabling more effective processing of slower signals. Both the numerical models and simultaneous recordings of membrane potential and Ca dynamics demonstrated that stochastic resonance is amplified by coupled electrical and Ca signaling, enhancing action potential generation at low noise levels. Adding noise currents to the cell and tissue numerical models allowed firing under conditions in which they otherwise would have stopped. SAN cells harness stochastic resonance amplified by coupled membrane-Ca signaling to ensure rhythmic heartbeat initiation, especially at low rates. This new signaling mechanism may help avoid sinus arrest when the heart slows and biological noise increases, such as during parasympathetic stimulation, bradyarrhythmia, or aging.
2026-07-06 | Cilostazol for Probable Swallow Syncope Associated With Sick Sinus Syndrome in a Nonagenarian Receiving Home-Based Care: A Case Report.
Swallow syncope is a rare reflex syncope, typically treated with pacemaker implantation. Pharmacological alternatives may be considered when pacemaker implantation is not feasible or not concordant with goals of care. We report a nonagenarian woman with dementia, very severe aortic stenosis, heart failure, and sick sinus syndrome who developed recurrent meal-triggered syncope after discharge. Holter monitoring documented multiple prolonged sinus pauses during hospitalization. Given frailty, comorbidities, and the family's preference to avoid rehospitalization, pacemaker implantation was not pursued. Cilostazol 100 mg twice daily was initiated in home-based care, resulting in complete resolution of syncope over 10 months without adverse effects. Cilostazol may represent a noninvasive therapeutic option for carefully selected patients with probable swallow syncope when pacemaker implantation is not concordant with goals of care.
gene therapies
2026-08-01 | SCN5A mutation – associated atrial cardiomyopathy unmasked by atrial flutter
The SCN5A gene encodes the voltage-gated sodium channel Nav1.5. Mutations in SCN5A are associated with various cardiac disorders, including Long QT syndrome type 3, Brugada syndrome, sick sinus syndrome, atrial fibrillation, progressive conduction system disease, multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy(1).
2026-07-31 | Percutaneous Atrial Delivery of TBX18 Creates a Stable Supraventricular Biological Pacemaker in Porcine Sick Sinus Syndrome.
Sick sinus syndrome (SSS) is caused primarily by sinoatrial node (SAN) dysfunction, often necessitating permanent pacemaker implantation. Although effective, electronic pacing has inherent limitations and hardware-related complications. Here, we developed a reproducible large-animal model of SSS to test the concept of "hardware-free" biological pacemaker therapy via percutaneous T-box transcription factor 18 (human) (TBX18) gene delivery. This study sought to create a preclinical model of SSS and rescue the phenoytpe by percutaneous delivery of TBX18 biological pacemaker. Healthy pigs underwent high-resolution electroanatomical mapping followed by targeted radiofrequency ablation of the SAN to induce sinus arrest. A backup electronic pacemaker was implanted to provide hemodynamic support. Two weeks postablation, after verification of SSS, the animals received percutaneous endovascular injection of either phosphate-buffered saline (n = 9) or TBX18 adenovirus (n = 9) into the lower atrial septum. Continuous electrocardiographic telemetry was performed for 4 weeks postinjection. By 2 weeks, TBX18-injected pigs exhibited higher intrinsic heart rates than controls (controls: 71.4 ± 4.0 beats/min vs TBX18: 96.3 ± 7.0 beats/min, P = 0.007) and reduced backup pacemaker use (P = 0.009). Heart rate variability analysis demonstrated improved rhythm stability in TBX18-injected animals (SD1/SD2, P = 0.0005), with fewer sinoatrial pauses and tachyarrhythmic episodes. Patch-clamp analysis of cells from the injection site revealed spontaneous action potentials and sinus node-like morphology, confirming the reprogramming of atrial myocytes into induced SAN-like cells. In this preclinical large-animal model of SSS, percutaneous TBX18 gene therapy successfully restored supraventricular pacemaker function, improved heart rate dynamics, and reduced reliance on electronic pacing. These findings support the use of biological pacemakers as a potential alternative to conventional device-based therapies for SSS.
2026-01-01 | Metabolic dysfunction associated kidney disease GWAS and gsMAP
Header Explanations:SNP: Single Nucleotide Polymorphism identifier (e.g., rsID).CHR: Chromosome number where the SNP is located.BP: Base pair position of the SNP on the chromosome.MAF: Minor Allele Frequency (frequency of the less common allele, 0–0.5).A2: Other allele (reference/non-effect allele).A1: Effect allele (allele for which the effect size is estimated).i: Index/iteration number (e.g., model or subgroup identifier).lhs: Left-hand side of the SEM equation (dependent variable, e.g., trait/factor).op: SEM operator (e.g., ~ = regression, =~ = latent measurement).rhs: Right-hand side of the SEM equation (independent variable, e.g., SNP).est: Regression coefficient estimate (effect size of SNP on lhs).se_c: Standard error of the coefficient estimate (est).Z_Estimate: Z-score for the estimate (est / se_c).Pval_Estimate: P-value for the estimate (significance of est).Q: Cochran’s Q statistic (measures heterogeneity of effects across subgroups/studies).Q_df: Degrees of freedom for the Q statistic.Q_pval: P-value for Cochran’s Q (significance of heterogeneity; <0.05 indicates significant heterogeneity).N_hat: Estimated effective sample size (total or weighted sample size used in analysis).
This folder contains gsMap output for the traits Atrial Fibrillation and Sick Sinus Syndrome on the MOSTA E16.5_E1S1 spatial transcriptomics sample. For each trait, there are three visualization subfolders: gsMap_plot/ (spatial maps showing where the trait-associated signal is enriched across the tissue section), GSS_plot/ (plots of Gene Specificity Score, GSS, illustrating where candidate genes are specifically expressed in space), and manhattan_plot/ (GWAS-style Manhattan/diagnostic plots summarizing genomic association signals). In addition, E16.5_E1S1.MOSTA_*_Gene_Diagnostic_Info.csv provides a gene-level diagnostic table (e.g., genes with their spatial annotation, summary GSS metrics such as median GSS, and correlation-style indicators linking spatial specificity to GWAS signal), while E16.5_E1S1.MOSTA_*_gsMap_Report.html is an integrated HTML report that brings together the key figures and summaries for quick interpretation and result review.
2025-11-01 | Indications for de novo pacemaker implantation, prognosis and complications in patients with and without type 2 diabetes mellitus
Abstract Background Patients with diabetes mellitus (DM) face higher risk of cardiovascular disease including arrythmias. Bradyarrhythmias are more frequent in patients with than those without DM and it seems like patients with DM have a higher need of pacemaker treatment compared to controls. The underlying mechanism behind this association is not fully explored. Purpose To assess differences in indications, complications, and outcomes between patients with and without type 2 DM (T2DM) with a newly implanted pacemaker. Methods This cohort study comprises adult patients who underwent de novo pacemaker implantation 2010–2021, using data from the Swedish ICD and Pacemaker Registry. Pacemaker indications (i.e.., etiology, ECG findings, symptoms) and complications during the first year after the implantation were analyzed using chi-square tests. T2DM was obtained from the Swedish National Diabetes Registry while comorbidities and outcomes like major adverse cardiovascular events (MACE) and all-cause mortality were evaluated by means of several national registries and Kaplan-Meier/Cox regressions models. Results Among 95,548 patients, 19% had T2DM before pacemaker implantation. T2DM patients had a mean DM duration of 12.8 years before the implantation. They were older (mean age 78.1 vs 76.7 years), overweight (mean BMI 29.4 kg/m²) and had a more frequent history of cardiovascular comorbidities compared to pacemaker patients without DM. Cardiac fibrosis (T2DM 80.3% vs. no DM 82.5%, p<0.0001) and ischemic heart disease (IHD) (9.5% vs. 6.0%, p<0.0001) were the most commonly reported reasons behind the need of pacemaker treatment. AV-block III and sick sinus syndrome were the most frequent ECG findings in both groups. Procedural complications were slightly lower in T2DM patients (4.0% vs. 4.3%, p<0.001), with electrode dislocation as the most common problem in both groups. The adjusted (patient demographics, IHD and heart failure) post implant risk of all-cause mortality (HR: 1.39, 95% CI [1.36-1.43]) and MACE (HR: 1.33, 95% CI [1.29-1.38]) was higher in patients with than without T2DM. Conclusions In patients undergoing pacemaker implantation, cardiac fibrosis is the most common underlying etiology irrespective of DM. T2DM was associated with a more dismal long-term outcome despite similar post-implant complication rates. Their elevated risks of all-cause mortality and MACE highlight the need for a comprehensive risk factor management to improve the prognosis.Cumulative risk for MACE Cumulative risk for all-cause mortality
2024-11-21 | Sex hormones and reproductive factors with cardiac arrhythmia and ECG indices: a mendelian randomization study.
Sex is a determinant of the incidence and etiology of arrhythmia. Observational and basic studies suggest that sex hormones are essential in this process; however, the relationship between sex hormones and arrhythmia remains unclear. Mendelian randomization (MR) was used to investigate the causal relationships between sex hormone levels, arrhythmia, and electrocardiographic (ECG) indices. Large genome-wide association studies (GWAS) data on sex hormones, stratified by sex, from the UK biobank consortium, were used as exposure data, and data on atrial fibrillation (AF), atrioventricular block, sick sinus syndrome, paroxysmal tachycardia, and ECG indices were obtained from the FinnGen consortium and summarized large GWAS data. Inverse variance weighting or wald odds was used as the primary analytical method, and weighted medians and MR-Egger regression were used for complementary analyses. The results of the MR of sex hormones and AF from different sources were analyzed using a meta-analysis. Summary-data-based MR analysis was utilized to explore the relationship between sex-hormone related drugs and arrhythmia. In men, genetically predicted higher estradiol concentrations were associated with a lower risk of AF (odds ratio: 0.908 [0.852-0.967]; p = 0.0029], whereas genetically predicted higher concentrations of total testosterone were associated with lower heart rate variability. Sex hormones showed no association with atrioventricular block, sick sinus syndrome, paroxysmal tachycardia, resting heart rate, P wave duration, P wave terminal force in lead V1 [PTFV1], PR interval, QRS duration, QTc [QT interval corrected by heart rate], ST duration, spatial [spQRSTa] and frontal [fQRSTa] QRS-T angles in males. In females, there was no significant evidence that sex hormones are associated with arrhythmias or ECG indices. In this study, we identified a potential causal relationship between estradiol and the risk of AF in males. However, there was no significant association between sex hormones and either arrhythmias or ECG indices in females. These results suggested that sex hormones may play a limited role in cardiac arrhythmias, which requires further verification.
proteins
2024-05-31 | Identification of pleiotropic and specific therapeutic targets for cardio-cerebral diseases: A large-scale proteome-wide mendelian randomization and colocalization study.
The cardiac-brain connection has been identified as the basis for multiple cardio-cerebral diseases. However, effective therapeutic targets for these diseases are still limited. Therefore, this study aimed to identify pleiotropic and specific therapeutic targets for cardio-cerebral diseases using Mendelian randomization (MR) and colocalization analyses. This study included two large protein quantitative trait loci studies with over 4,000 plasma proteins were included in the discovery and replication cohorts, respectively. We initially used MR to estimate the associations between protein and 20 cardio-cerebral diseases. Subsequently, Colocalization analysis was employed to enhance the credibility of the results. Protein target prioritization was based solely on including highly robust significant results from both the discovery and replication phases. Lastly, the Drug-Gene Interaction Database was utilized to investigate protein-gene-drug interactions further. A total of 46 target proteins for cardio-cerebral diseases were identified as robust in the discovery and replication phases by MR, comprising 7 pleiotropic therapeutic proteins and 39 specific target proteins. Followed by colocalization analysis and prioritization of evidence grades for target protein, 6 of these protein-disease pairs have achieved the highly recommended level. For instance, the PILRA protein presents a pleiotropic effect on sick sinus syndrome and Alzheimer's disease, whereas GRN exerts specific effects on the latter. APOL3, LRP4, and F11, on the other hand, have specific effects on cardiomyopathy and ischemic stroke, respectively. This study successfully identified important therapeutic targets for cardio-cerebral diseases, which benefits the development of preventive or therapeutic drugs.
2011-04-04 | Coordinating electrical activity of the heart: ankyrin polypeptides in human cardiac disease
Introduction: Over the past ten years, ankyrin polypeptides have emerged as players in cardiac excitation–contraction coupling. Once thought to solely play a structural role, loss-of-function variants of genes encoding ankyrin polypeptides have highlighted how this protein mediates subcellular localization of various electrical components of the excitation–contraction coupling machinery. Evidence has revealed how disruption of this localization is the primary cause of various cardiomyopathies, ranging from long-QT syndrome 4, to sinus node disease, to more common forms of arrhythmias. Areas covered: The roles of ankyrin polypeptides in excitation–contraction coupling in the heart and the development of ankyrin-specific cardiomyopathies. How ankyrin polypeptides may be involved in structural and electrical remodeling of the heart, post-myocardial infarct. How ankyrin interactions with membrane-bound ion channels may regulate these channels' response to stimuli. New data, which offers the potential for unique therapies, for not only combating heart disease, but also for wider applications to various disease states. Expert opinion: The ankyrin family of adapter proteins is emerging as an intimate player in cardiac excitation–contraction coupling. Until recently, these proteins have gone largely unappreciated for their importance in proper cardiac function. New insights into how these proteins function within the heart are offering potentially new avenues for therapies against cardiomyopathy.
cell therapies
2026-09-23 | The role of atrioventricular delay in left bundle branch stimulation: when diastole is more important than systole
We present a clinical case of an 86yearold patient with initially preserved left ventricular ejection fraction, left bundle branch block, and sick sinus syndrome, who underwent implantation of a dualchamber pacemaker with selective left bundle branch pacing. With a programmed short atrioventricular delay (100/120 ms) and a high percentage of ventricular pacing, progression of chronic heart failure, a decrease in left ventricular ejection fraction, and worsening exercise tolerance were observed, without signs of myocardial ischemia, significant tachyarrhythmia, or loss of conduction system capture. Using echocardiographic parameters according to Ritter’s method, an optimal atrioventricular interval was selected, which resulted in restoration of atrioventricular synchrony and an increase in left ventricular ejection fraction.
2026-06-29 | First dual-chamber leadless pacemaker implantation at Meitra United Heart Centre, Kasaragod: a regional milestone in an octogenarian with sick sinus syndrome: a case report
Leadless pacemaker technology has advanced to enable dual-chamber atrioventricular synchronous pacing through implant-to-implant communication between two independent leadless devices. We report the first AVEIR dual-chamber leadless pacemaker implantation performed at Meitra United Heart Centre (MUHC), marking a regional milestone for Kasaragod, Kannur, Coastal Karnataka, and Goa. An 86-year-old woman presented with sick sinus syndrome complicated by tachy-brady syndrome and presyncopal episodes. She underwent successful implantation of a dual-chamber leadless pacemaker via femoral venous access under general anesthesia using the Innvolution Pinnacle Agile Cath Lab at MUHC. Optimal electrical parameters were achieved, with a right ventricular threshold of 0.5 V at 0.4 ms and impedance of 750 Ω, and a right atrial threshold of 1.0 V at 0.4 ms and impedance of 310 Ω. Device-to-device communication was 100%. Postoperatively, the patient developed left femoral vein thrombosis, which was managed with anticoagulation therapy, and she was discharged in stable condition. This case demonstrates that dual-chamber leadless pacing is feasible in an octogenarian with sick sinus syndrome and may serve as an alternative to conventional transvenous pacing systems, while emphasizing the need to consider vascular access complications such as femoral vein thrombosis during patient selection.
2026-02-24 | Upgrading expandable leadless pacemakers from single- to dual-chamber.
The aim of this analysis was to evaluate the upgradeability of a single-chamber leadless pacemaker (LP) to a dual-chamber system in patients indicated for a dual-chamber pacemaker. A prospective, multicentre study evaluated the safety and performance of a dual-chamber LP. The study included patients with a prior ventricular LP to evaluate its upgradeability. Patients had an attempted atrial LP implant, and if successfully implanted, the LPs were paired to a dual-chamber pacing mode to evaluate upgrade success. Patients were followed for 12 months from the attempted atrial LP implantation. Among 35 patients with an attempted upgrade (62.9% male, average age 70 years), the most common primary indication was sinus node dysfunction (57.1%). Out of 35 patients, 91.4% had successful upgrades. The mean atrial device electrical measurements stabilized within 1 month from the procedure and remained stable through 12 months (capture threshold at 0.4 ms 0.8 ± 0.6 V, sense amplitude 4.5 ± 2.7 mV at 12 months). A total of five (14.3%) patients experienced seven complications, all of which were procedure-related. There were no device or procedure-related deaths. The total estimated battery longevity (accounting for time since implant) evaluated at 12 months was 11.3 ± 4.2 and 5.7 ± 2.6 years for the ventricular and atrial LPs, respectively. One patient required an atrial LP revision 10 months after implantation. The LP was retrieved and replaced. These data confirm the feasibility, safety, and long-term effectiveness of adding an atrial LP in patients with a pre-existing ventricular LP to achieve dual-chamber leadless pacing.
2026-01-01 | Evaluation of the Feasibility and Safety of Left Ventricular Pacing Using Left Bundle Branch Area Pacing (LBBAP) Without Backup Right Ventricular Pacing Lead
All articles of this category (opens in new window) Background: This study aims to evaluate the feasibility and safety of sole left ventricular pacing using left bundle branch area pacing (LBBAP) without a backup right ventricular lead. Methods: Patients who were over 18 years old and received a pacemaker with left bundle branch area pacing (LBBAP) with no additional right ventricular lead implantation from June 2023 through October 2024 in a single center were included. Patients with incomplete documentation and those who failed to provide informed consent were excluded. Preoperative, intraoperative, and postoperative data were retrospectively collected. A prospective follow-up with determination of changes in Rheobase, lead impedance, and sensing (postoperatively, at 6 weeks, and at 6 months) was documented, as well as lead dislocation or pacemaker-related complications. NT-pro-BNP values were evaluated 6 months after implantation. Results: A total of 42 patients were included, with a mean age of 77 ± 10 years, 68% males, 83% in sinus rhythm, mean EF of 54 ± 7%. The main indication was a third-degree AV-Block (34%), bradycardia-tachycardia syndrome (24%) sick sinus syndrome (24%). The mean operative time was 60 ± 10 minutes. The mean radiation dose was 1,103 ± 561 (cGy) cm 2 The LBBAP QRS time was 112 ms. Three patients suffered a postoperative hematoma and were treated conservatively. Two patients suffered a dislocation of the LBBA lead, and they were repositioned. During follow-up, one patient died of pneumonia. The follow-up data were complete for the remaining 41 patients. There were no late dislocations or pacemaker-related complications. The Rheobase significantly increased from a mean of 0.55 mV after implantation to 0.82 mV after 6 weeks ( p < 0.001) and did not change significantly after 6 months (0.82 vs. 0.69 mV, respectively, p > 0.999). The mean electrode impedance improved significantly after 6 weeks (391 vs. 469 Ohm perioperatively, p = 0.02) and did not change significantly after 6 months. The sensing did not change significantly over time (11.8 vs. 12.3 vs. 12.2 mV; p = 0.085). The NT-proBNP did not change significantly over 6 months (1,422 vs. 2,001 pg/mL ; p = 0.764). Conclusion: LBBAP is a safe and stable approach that provides a more physiological pacing. The pacing electrodes are stable, their parameters stay stable over time, and a dislocation is only seen perioperatively. A backup right ventricular lead may not be needed with increased experience, yet longer perioperative monitoring might be warranted to exclude perioperative dislocation. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-12-10 | Platelet-bioengineered hiPSC-sEVs achieve targeted repair of fibrotic sinoatrial node in preclinical SND models.
Sinus node dysfunction, a prevalent arrhythmia in aging populations, is characterized by fibrosis and loss of pacemaker activity, necessitating pacemaker implantation. Current therapies fail to reverse the underlying pathology. Small extracellular vesicles derived from human induced pluripotent stem cells possess regenerative potential but lack targeted delivery. Here, we engineer platelet membrane-fused vesicles that synergistically combine collagen targeting for ischemic injury homing with immune evasion. In a rat model of sinus node dysfunction, these modified vesicles exhibit 3.1-fold higher accumulation in the sinoatrial node compared to unmodified vesicles, resulting in a 63% reduction in fibrosis and significant restoration of heart rate and intrinsic pacemaker function. The vesicles mitigate fibroblast activation and protect cardiomyocytes from oxidative stress. This study establishes a targeted, cell-free nanotherapeutic platform for resolving fibrosis and electrophysiological dysfunction in sinus node disease.
small molecules
2026-08-13 | Expression Defects of SCN5A Common Polymorphisms S524Y and H558R in the Q1077 Splice Variant Can Be Rescued by Mexiletine.
The cardiac sodium channel NaV1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of NaV1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine "rescued" expression deficiencies in the Brugada syndrome. Cells expressing S524Y/Q1077 and H558R/Q1077 were incubated for 48 h with or without mexiletine (500 μM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y/Q1077 and H558R/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms.
2026-08-12 | Efficacy and safety of Lingbao Huxin Dan in the treatment of sick sinus syndrome: a randomized, single-blind, placebo-controlled, crossover trial
Background Permanent pacemaker implantation is the standard treatment for symptomatic sick sinus syndrome (SSS), but it does not reverse the underlying sinus node dysfunction. Lingbao Huxin Dan (LBHXD) may benefit patients with bradyarrhythmia. However, robust clinical evidence regarding its efficacy and safety in patients with SSS, particularly those with pacemakers, is lacking. Methods A randomized, crossover trial was conducted. Thirty patients with SSS and implanted DDD pacemakers were enrolled and randomly assigned to one of two treatment sequences: LBHXD followed by placebo, or placebo followed by LBHXD. Each treatment period lasted 4 weeks, separated by a 2-week washout interval. Results 25 patients completed the trial. Following propensity score matching, 17 patients were included in the final analysis. Compared to the placebo phase, LBHXD administration resulted in a significantly greater reduction in AP% (38.99% ± 20.67% vs. 48.03% ± 21.95%, P < 0.01). LBHXD also significantly increased several HRV indices, including SDNN, SDANN, rMSSD, and SDNN index (all P < 0.05), and elevated the mean and maximum HR ( P < 0.05). No significant changes were observed in ventricular pacing percentage, left atrial diameter, or left ventricular ejection fraction. Conclusion Adjunctive therapy with Lingbao Huxin Dan can effectively reduce atrial pacing dependency, improve heart rate variability, and increase heart rate in patients with SSS and pacemakers, demonstrating a favorable safety profile. These findings suggest that LBHXD may enhance intrinsic sinoatrial node function and autonomic regulation, supporting its potential role as a complementary therapy in an integrative medicine approach to managing SSS. Clinical Trial Registration https://www.chictr.org.cn/showproj.html?proj=187346 , Chinese Clinical Trial Registry ChiCTR2300067497.
2026-08-04 | The Effect of Psychotropic Agents on Sick Sinus Syndrome: A Case Report
Sick sinus syndrome (SSS) presents significant challenges in psychiatric medication management because of the potential for worsening cardiac conduction and interactions with antiarrhythmic therapy. A 35-year-old woman with generalized anxiety disorder (GAD) and insomnia was treated with bupropion, hydroxyzine, melatonin, and intermittent quetiapine, alongside comorbid SSS and supraventricular tachycardia managed post-ablation with metoprolol. A review of her regimen identified several cardiac safety concerns: quetiapine’s potential interference with flecainide, hydroxyzine-associated QT prolongation, and bupropion’s CYP2D6 inhibition that could increase flecainide levels. Management prioritized minimizing arrhythmogenic risk by discontinuing quetiapine, restricting hydroxyzine to low doses, and continuing melatonin, supplemented by stress testing and reassessment of psychotropic options. This case highlights the importance of careful psychotropic selection in patients with SSS, favoring lower-risk agents, such as mirtazapine, which is one of the safest among several possible alternatives, while maintaining close ECG monitoring and coordinated cardiology and psychiatry collaboration to reduce drug-drug interactions and optimize safety.
2026-07-15 | Cardiac Pacemaker Cells Harness Stochastic Resonance to Avoid Sinus Arrest.
The sinoatrial node (SAN) is the primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials exiting the SAN emerge from heterogeneous signals, including subthreshold signals in nonfiring (dormant) cells. This raises a new question in cardiac biology: how do these signals contribute to heartbeat generation? Here, we tested the hypothesis that pacemaker cells harness stochastic resonance to ensure fail-safe operation, especially at low rates bordering on sinus arrest. Membrane potential and Ca signals were measured using perforated-patch recordings in rabbit SAN cells exposed to sine-wave or white-noise currents. In addition, we imaged Ca signals in intact mouse SAN tissue and performed multiscale model simulations at the subcellular, cellular, and tissue levels. In addition to synchronized Ca transients, SAN tissue exhibited heterogeneous local Ca signals with different kinetics. Noise currents, mimicking the heterogeneous natural cellular environment, restored action potential firing in dormant cells and substantially improved the rate and rhythm of cells firing infrequently and irregularly. Performance followed a bell-shaped curve, peaking and then declining, demonstrating a hallmark of stochastic resonance. Rhythmic action potential generation in response to sine-wave currents of different frequencies defined a resonance spectrum in SAN cells, reflecting their ability to respond via stochastic resonance to specific frequency components embedded in noise. Cholinergic stimulation shifted the resonance spectrum and responses to noise toward lower frequencies across all amplitudes tested, rendering cells unresponsive to higher-frequency signals while enabling more effective processing of slower signals. Both the numerical models and simultaneous recordings of membrane potential and Ca dynamics demonstrated that stochastic resonance is amplified by coupled electrical and Ca signaling, enhancing action potential generation at low noise levels. Adding noise currents to the cell and tissue numerical models allowed firing under conditions in which they otherwise would have stopped. SAN cells harness stochastic resonance amplified by coupled membrane-Ca signaling to ensure rhythmic heartbeat initiation, especially at low rates. This new signaling mechanism may help avoid sinus arrest when the heart slows and biological noise increases, such as during parasympathetic stimulation, bradyarrhythmia, or aging.
2026-07-06 | Cilostazol for Probable Swallow Syncope Associated With Sick Sinus Syndrome in a Nonagenarian Receiving Home-Based Care: A Case Report.
Swallow syncope is a rare reflex syncope, typically treated with pacemaker implantation. Pharmacological alternatives may be considered when pacemaker implantation is not feasible or not concordant with goals of care. We report a nonagenarian woman with dementia, very severe aortic stenosis, heart failure, and sick sinus syndrome who developed recurrent meal-triggered syncope after discharge. Holter monitoring documented multiple prolonged sinus pauses during hospitalization. Given frailty, comorbidities, and the family's preference to avoid rehospitalization, pacemaker implantation was not pursued. Cilostazol 100 mg twice daily was initiated in home-based care, resulting in complete resolution of syncope over 10 months without adverse effects. Cilostazol may represent a noninvasive therapeutic option for carefully selected patients with probable swallow syncope when pacemaker implantation is not concordant with goals of care.
gene therapies
2026-08-01 | SCN5A mutation – associated atrial cardiomyopathy unmasked by atrial flutter
The SCN5A gene encodes the voltage-gated sodium channel Nav1.5. Mutations in SCN5A are associated with various cardiac disorders, including Long QT syndrome type 3, Brugada syndrome, sick sinus syndrome, atrial fibrillation, progressive conduction system disease, multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy(1).
2026-07-31 | Percutaneous Atrial Delivery of TBX18 Creates a Stable Supraventricular Biological Pacemaker in Porcine Sick Sinus Syndrome.
Sick sinus syndrome (SSS) is caused primarily by sinoatrial node (SAN) dysfunction, often necessitating permanent pacemaker implantation. Although effective, electronic pacing has inherent limitations and hardware-related complications. Here, we developed a reproducible large-animal model of SSS to test the concept of "hardware-free" biological pacemaker therapy via percutaneous T-box transcription factor 18 (human) (TBX18) gene delivery. This study sought to create a preclinical model of SSS and rescue the phenoytpe by percutaneous delivery of TBX18 biological pacemaker. Healthy pigs underwent high-resolution electroanatomical mapping followed by targeted radiofrequency ablation of the SAN to induce sinus arrest. A backup electronic pacemaker was implanted to provide hemodynamic support. Two weeks postablation, after verification of SSS, the animals received percutaneous endovascular injection of either phosphate-buffered saline (n = 9) or TBX18 adenovirus (n = 9) into the lower atrial septum. Continuous electrocardiographic telemetry was performed for 4 weeks postinjection. By 2 weeks, TBX18-injected pigs exhibited higher intrinsic heart rates than controls (controls: 71.4 ± 4.0 beats/min vs TBX18: 96.3 ± 7.0 beats/min, P = 0.007) and reduced backup pacemaker use (P = 0.009). Heart rate variability analysis demonstrated improved rhythm stability in TBX18-injected animals (SD1/SD2, P = 0.0005), with fewer sinoatrial pauses and tachyarrhythmic episodes. Patch-clamp analysis of cells from the injection site revealed spontaneous action potentials and sinus node-like morphology, confirming the reprogramming of atrial myocytes into induced SAN-like cells. In this preclinical large-animal model of SSS, percutaneous TBX18 gene therapy successfully restored supraventricular pacemaker function, improved heart rate dynamics, and reduced reliance on electronic pacing. These findings support the use of biological pacemakers as a potential alternative to conventional device-based therapies for SSS.
2026-01-01 | Metabolic dysfunction associated kidney disease GWAS and gsMAP
Header Explanations:SNP: Single Nucleotide Polymorphism identifier (e.g., rsID).CHR: Chromosome number where the SNP is located.BP: Base pair position of the SNP on the chromosome.MAF: Minor Allele Frequency (frequency of the less common allele, 0–0.5).A2: Other allele (reference/non-effect allele).A1: Effect allele (allele for which the effect size is estimated).i: Index/iteration number (e.g., model or subgroup identifier).lhs: Left-hand side of the SEM equation (dependent variable, e.g., trait/factor).op: SEM operator (e.g., ~ = regression, =~ = latent measurement).rhs: Right-hand side of the SEM equation (independent variable, e.g., SNP).est: Regression coefficient estimate (effect size of SNP on lhs).se_c: Standard error of the coefficient estimate (est).Z_Estimate: Z-score for the estimate (est / se_c).Pval_Estimate: P-value for the estimate (significance of est).Q: Cochran’s Q statistic (measures heterogeneity of effects across subgroups/studies).Q_df: Degrees of freedom for the Q statistic.Q_pval: P-value for Cochran’s Q (significance of heterogeneity; <0.05 indicates significant heterogeneity).N_hat: Estimated effective sample size (total or weighted sample size used in analysis).
This folder contains gsMap output for the traits Atrial Fibrillation and Sick Sinus Syndrome on the MOSTA E16.5_E1S1 spatial transcriptomics sample. For each trait, there are three visualization subfolders: gsMap_plot/ (spatial maps showing where the trait-associated signal is enriched across the tissue section), GSS_plot/ (plots of Gene Specificity Score, GSS, illustrating where candidate genes are specifically expressed in space), and manhattan_plot/ (GWAS-style Manhattan/diagnostic plots summarizing genomic association signals). In addition, E16.5_E1S1.MOSTA_*_Gene_Diagnostic_Info.csv provides a gene-level diagnostic table (e.g., genes with their spatial annotation, summary GSS metrics such as median GSS, and correlation-style indicators linking spatial specificity to GWAS signal), while E16.5_E1S1.MOSTA_*_gsMap_Report.html is an integrated HTML report that brings together the key figures and summaries for quick interpretation and result review.
2025-11-01 | Indications for de novo pacemaker implantation, prognosis and complications in patients with and without type 2 diabetes mellitus
Abstract Background Patients with diabetes mellitus (DM) face higher risk of cardiovascular disease including arrythmias. Bradyarrhythmias are more frequent in patients with than those without DM and it seems like patients with DM have a higher need of pacemaker treatment compared to controls. The underlying mechanism behind this association is not fully explored. Purpose To assess differences in indications, complications, and outcomes between patients with and without type 2 DM (T2DM) with a newly implanted pacemaker. Methods This cohort study comprises adult patients who underwent de novo pacemaker implantation 2010–2021, using data from the Swedish ICD and Pacemaker Registry. Pacemaker indications (i.e.., etiology, ECG findings, symptoms) and complications during the first year after the implantation were analyzed using chi-square tests. T2DM was obtained from the Swedish National Diabetes Registry while comorbidities and outcomes like major adverse cardiovascular events (MACE) and all-cause mortality were evaluated by means of several national registries and Kaplan-Meier/Cox regressions models. Results Among 95,548 patients, 19% had T2DM before pacemaker implantation. T2DM patients had a mean DM duration of 12.8 years before the implantation. They were older (mean age 78.1 vs 76.7 years), overweight (mean BMI 29.4 kg/m²) and had a more frequent history of cardiovascular comorbidities compared to pacemaker patients without DM. Cardiac fibrosis (T2DM 80.3% vs. no DM 82.5%, p<0.0001) and ischemic heart disease (IHD) (9.5% vs. 6.0%, p<0.0001) were the most commonly reported reasons behind the need of pacemaker treatment. AV-block III and sick sinus syndrome were the most frequent ECG findings in both groups. Procedural complications were slightly lower in T2DM patients (4.0% vs. 4.3%, p<0.001), with electrode dislocation as the most common problem in both groups. The adjusted (patient demographics, IHD and heart failure) post implant risk of all-cause mortality (HR: 1.39, 95% CI [1.36-1.43]) and MACE (HR: 1.33, 95% CI [1.29-1.38]) was higher in patients with than without T2DM. Conclusions In patients undergoing pacemaker implantation, cardiac fibrosis is the most common underlying etiology irrespective of DM. T2DM was associated with a more dismal long-term outcome despite similar post-implant complication rates. Their elevated risks of all-cause mortality and MACE highlight the need for a comprehensive risk factor management to improve the prognosis.Cumulative risk for MACE Cumulative risk for all-cause mortality
2024-11-21 | Sex hormones and reproductive factors with cardiac arrhythmia and ECG indices: a mendelian randomization study.
Sex is a determinant of the incidence and etiology of arrhythmia. Observational and basic studies suggest that sex hormones are essential in this process; however, the relationship between sex hormones and arrhythmia remains unclear. Mendelian randomization (MR) was used to investigate the causal relationships between sex hormone levels, arrhythmia, and electrocardiographic (ECG) indices. Large genome-wide association studies (GWAS) data on sex hormones, stratified by sex, from the UK biobank consortium, were used as exposure data, and data on atrial fibrillation (AF), atrioventricular block, sick sinus syndrome, paroxysmal tachycardia, and ECG indices were obtained from the FinnGen consortium and summarized large GWAS data. Inverse variance weighting or wald odds was used as the primary analytical method, and weighted medians and MR-Egger regression were used for complementary analyses. The results of the MR of sex hormones and AF from different sources were analyzed using a meta-analysis. Summary-data-based MR analysis was utilized to explore the relationship between sex-hormone related drugs and arrhythmia. In men, genetically predicted higher estradiol concentrations were associated with a lower risk of AF (odds ratio: 0.908 [0.852-0.967]; p = 0.0029], whereas genetically predicted higher concentrations of total testosterone were associated with lower heart rate variability. Sex hormones showed no association with atrioventricular block, sick sinus syndrome, paroxysmal tachycardia, resting heart rate, P wave duration, P wave terminal force in lead V1 [PTFV1], PR interval, QRS duration, QTc [QT interval corrected by heart rate], ST duration, spatial [spQRSTa] and frontal [fQRSTa] QRS-T angles in males. In females, there was no significant evidence that sex hormones are associated with arrhythmias or ECG indices. In this study, we identified a potential causal relationship between estradiol and the risk of AF in males. However, there was no significant association between sex hormones and either arrhythmias or ECG indices in females. These results suggested that sex hormones may play a limited role in cardiac arrhythmias, which requires further verification.
proteins
2024-05-31 | Identification of pleiotropic and specific therapeutic targets for cardio-cerebral diseases: A large-scale proteome-wide mendelian randomization and colocalization study.
The cardiac-brain connection has been identified as the basis for multiple cardio-cerebral diseases. However, effective therapeutic targets for these diseases are still limited. Therefore, this study aimed to identify pleiotropic and specific therapeutic targets for cardio-cerebral diseases using Mendelian randomization (MR) and colocalization analyses. This study included two large protein quantitative trait loci studies with over 4,000 plasma proteins were included in the discovery and replication cohorts, respectively. We initially used MR to estimate the associations between protein and 20 cardio-cerebral diseases. Subsequently, Colocalization analysis was employed to enhance the credibility of the results. Protein target prioritization was based solely on including highly robust significant results from both the discovery and replication phases. Lastly, the Drug-Gene Interaction Database was utilized to investigate protein-gene-drug interactions further. A total of 46 target proteins for cardio-cerebral diseases were identified as robust in the discovery and replication phases by MR, comprising 7 pleiotropic therapeutic proteins and 39 specific target proteins. Followed by colocalization analysis and prioritization of evidence grades for target protein, 6 of these protein-disease pairs have achieved the highly recommended level. For instance, the PILRA protein presents a pleiotropic effect on sick sinus syndrome and Alzheimer's disease, whereas GRN exerts specific effects on the latter. APOL3, LRP4, and F11, on the other hand, have specific effects on cardiomyopathy and ischemic stroke, respectively. This study successfully identified important therapeutic targets for cardio-cerebral diseases, which benefits the development of preventive or therapeutic drugs.
2011-04-04 | Coordinating electrical activity of the heart: ankyrin polypeptides in human cardiac disease
Introduction: Over the past ten years, ankyrin polypeptides have emerged as players in cardiac excitation–contraction coupling. Once thought to solely play a structural role, loss-of-function variants of genes encoding ankyrin polypeptides have highlighted how this protein mediates subcellular localization of various electrical components of the excitation–contraction coupling machinery. Evidence has revealed how disruption of this localization is the primary cause of various cardiomyopathies, ranging from long-QT syndrome 4, to sinus node disease, to more common forms of arrhythmias. Areas covered: The roles of ankyrin polypeptides in excitation–contraction coupling in the heart and the development of ankyrin-specific cardiomyopathies. How ankyrin polypeptides may be involved in structural and electrical remodeling of the heart, post-myocardial infarct. How ankyrin interactions with membrane-bound ion channels may regulate these channels' response to stimuli. New data, which offers the potential for unique therapies, for not only combating heart disease, but also for wider applications to various disease states. Expert opinion: The ankyrin family of adapter proteins is emerging as an intimate player in cardiac excitation–contraction coupling. Until recently, these proteins have gone largely unappreciated for their importance in proper cardiac function. New insights into how these proteins function within the heart are offering potentially new avenues for therapies against cardiomyopathy.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.