Sinus Node Dysfunction Research Articles

Case report: Successful implantation of atrial lead in Marshall vein in a patient with sinus node dysfunction.

This case demonstrates that utilizing the vein of Marshall as an alternative option for atrial lead implantation is both safe and effective when encountering challenges during atrial lead implantation.

Prognostic parameters predict cardiac events in Brugada syndrome: a meta-analysis

Abstract Background Brugada syndrome (BrS) is recognized as a cause of sudden cardiac death (SCD), ventricular tachycardia or ventricular fibrillation (VT/VF). However, the prognosis varies among the patients with Brugada electrocardiograph (ECG) pattern. Furthermore, there is no prognostic tool to predict the worsening cardiac outcomes in BrS. Objectives Primary outcome was to assess the association between risks including patient history, ECG pattern, electrophysiology study (EPS) findings and cardiac events which is identified as VT/VF or SCD. Method We performed a meta-analysis of prospective and retrospective cohort studies which assessed the risks and cardiac events in patients with BrS. Pooled hazard ratios (HRs) was analyzed by using Random-effect model. Result A total of 27 studies involving 15,990 BrS patients. Of these, 17 were retrospective studies and 10 were prospective studies. In univariate analysis, the risks including male, aborted SCD, QRS duration≥120 msec, fragmented QRS (multiple spikes within the QRS complex in lead V1-V3), late potential (positive terminal filtered QRS complex of signal-averaged ECG), sinus node dysfunction or inducibility of ventricular tachyarrhythmias during EPS associated with a higher risk of cardiac events in BrS. In multivariate analysis, higher risks of cardiac events were associated in BrS patients with history of syncope (HR 2.65, 95% confidence interval (CI): 1.68-4.19, I2 = 54 %, p-value <0.001), family history of SCD (HR 2.64, 95%CI:1.39-5.01, I2 = 0%, p-value = 0.003), prior VF (HR 14.52, 95%CI: 3.36-62.84, I2 = 62%, p-value <0.001), type 1 Brugada ECG pattern (HR 2.07, 95%CI: 1.13-3.79, I2 = 0%, p-value = 0.018), spontaneous type 1 ECG pattern (HR 1.91, 95%CI: 1.01-3.61, I2 = 58%, p-value = 0.046), early repolarization pattern (HR 2.78, 95%CI: 1.9-4.07, I2 = 0%, p-value < 0.001) and history of atrial fibrillation before BrS diagnosis (HR 1.82, 95%CI: 1.03-3.23, I2 = 49%, p-value = 0.039) (Table 1). Conclusion Our findings suggest that patient history, ECG pattern, EPS findings can predict the cardiac events. Introducing a risk prediction model could aid in early management of BrS.

Phenotype groups in atrial cardiomyopathy and their prognosis

Abstract Background Atrial cardiomyopathy (ACM) includes patients with heterogenous demographic characteristics and comorbidities. Defining phenotype groups with similar clinical characteristics is important for the effective treatment of these patients, and for their prognosis and prevention of ACM. Purpose To conduct a cluster analysis that could help us in phenotyping ACM and exploring the clinical complexity of this entity. Methods We performed a hierarchical cluster analysis based on Ward’s Method using 10 clinical binary variables (hypertension, diabetes mellitus, heart failure, obesity, chronic obstructive pulmonary disease, cancer, coronary artery disease, sinus node dysfunction or atrio-ventricular block, implanted pacemaker, and ischemic stroke), identifying the optimal number of clusters. We investigated differences in demographic, laboratory and echocardiographic parameters, and treatment between defined clusters, and assessed the impact of these factors on prognosis. Results Of 724 evaluated consecutive patients with dilated left atrium only 200 met the criteria for advanced atrial cardiomyopathy, defined as severely dilated left atrium with volume index (LAVI) ≥ 48 ml/m2, preserved left ventricular systolic function - ejection fraction ≥ 50%, without an overt valvular or ventricular disease, and were included in the analysis. Mean age of the studied population was 73.91 ± 9.74 years, 58 % of them were women. We identified 4 clusters: cluster 1 (n = 73, 36%) were younger overweight patients with paroxysmal atrial fibrillation (AF); cluster 2 (n = 56, 28%) - old patients with congestive heart failure (CHF) and low body mass index (BMI); cluster 3 (n = 34, 17%)- diabetic patients with obesity and CHF; and cluster 4 (n = 37, 19%) old patients with tachycardia-bradycardia syndrome, implanted pacemakers, and long -standing AF. Over a mean follow up of 20.6 months cluster 2 had the highest mortality rate (28.6%), followed by cluster 3 (20.6%), compared to the lower mortality rate of cluster 1 and 4 (11% and 10.8%, respectively, p=0.047). The presence of heart failure (HR 4.4, CI 1.5 ÷12.7, p=0.006), cancer (HR 3.3, CI 1.6 ÷ 6.9, p=0.002) and greater than moderate tricuspid regurgitation (HR 5.4, CI 2.6 ÷ 11.3, p<0.001) were predictors of poor outcome. Conclusion In patients with advanced atrial cardiomyopathy, four main clusters were identified, differentiated by distinct comorbidities. Both clinical and echocardiographic parameters were found to be associated with an increased risk of mortality.Phenotype clusters of ACMKaplan-Meier curves of clusters

Conduction-System pacing Italian Network Group (C-SING): insights from a Nationwide Multicenter Observational Study

Abstract Background/Introduction Conduction system pacing (CSP), encompassing His bundle pacing (HBP) and left bundle branch area pacing (LBBAP), has gained prominence in treating bradycardia and heart failure in recent years. Despite its increasing utilization, data on real-world adoption of CSP are limited. Purpose The C-SING study aimed at assessing patient characteristics, implant success, procedural details, and safety of CSP when performed in routine clinical practice. Methods Periprocedural data from 27 experienced CSP centers across Italy were collected on patients undergoing CSP implantation for various indications between January 2021 and January 2024. Results The study comprised 1,317 patients (median age 78 years [interquartile range, 71-83], male 66.2%). Leading indications included atrioventricular (AV) block (40.8%), sinus node dysfunction (12.1%), atrial fibrillation with bradycardia (9.7%), AV node ablation (9.5%), and heart failure (12.5%). Pacemakers were implanted in 77.3% of patients, cardiac resynchronization devices in 21.7%, and implantable cardioverter-defibrillators in 1.0%. Stylet-driven and lumenless CSP leads were utilized in 64.7% and 35.3% of procedures, respectively. Final 12-lead ECG assessment revealed LBBAP capture in 88.7% patients, HBP in 8.4% (selective 4.2%, non-selective 4.2%), and no CSP capture in 3.0%, resulting in a 97.0% CSP lead implantation success rate. In patients with LBBAP, predominant capture types were left bundle branch pacing (19.6%), left posterior fascicular pacing (19.2%), and left septal fascicular pacing (14.8%). Comparing HBP to LBBAP, the latter showed shorter procedural time (60 minutes [45-80] vs. 70 minutes [60-95], p=0.003), but similar fluoroscopy time (6.0 minutes [3.3-10.8] vs. 6.1 minutes [4-10], p=0.735). Paced QRS duration was longer in LBBAP (118 ms [105-130]) compared to HBP (110 ms [101-122], p<0.001). LBBAP showed lower capture thresholds (0.6 V [0.5-0.9] @0.4 ms vs. 0.8 V [0.5-1.5] @1.0 ms, p<0.001) and higher R-wave sensing (10.7 mV [8-16] vs. 4.5 mV [2.4-9.9], p<0.001). The rate of periprocedural complications was higher in patients with LBBAP than HBP (7.3% vs. 1.8%, p=0.03), with the most frequent events being intraprocedural perforation into the left ventricular cavity during lead screwing (2.6%) and CSP lead dislodgment before hospital discharge (1.4%). These occurrences necessitated lead repositioning without additional complications. Conclusion CSP demonstrated feasibility as a primary pacing strategy for various indications in a real-world, multicenter setting. LBBAP, more frequently used than HBP, exhibited shorter procedural time and superior acute electrical parameters. LBBAP revealed a higher rate of minor procedural complications than HBP. Further investigations, supported by additional long-term outcome data, are essential to comprehensively assess CSP performance.

Intracardiac leadless pacemaker: long term safety over traditional pacemakers. a systematic review and meta-analysis

Abstract Introduction Leadless pacemaker (LP) is a novel technology designed to reduce lead-related, including pocket infections, associated with traditional pacemakers. LP can be used in patients with high-degree AV block, sinus node dysfunction, and bradycardia with syncope. We conducted a systematic review and meta-analysis to examine the long-term safety of intra-cardiac leadless pacemakers compared with traditional pacemakers. Methods Our protocol was registered in advance on PROSPERO. Studies were eligible if they compared complications, revision, cardiac perforation, infections, and all-cause mortality between patients who received leadless pacemakers versus traditional pacemakers. The systematic search was conducted in five databases (MEDLINE, EMBASE, CENTRAL, Web of Science, Scopus) without restriction. The random-effect model was implemented to calculate pooled odds ratio (OR) with a 95% confidence interval (CI). Also, the Mantel-Haenszel method, Paule-Mandel estimator for tau^2, Q-Profile method for the confidence interval of tau^2 and tau, and Hartung-Knapp adjustment for random effects model methods were used for the prediction of data extracted directly from the curves. ROBINS-I tool was used for the risk of bias assessment, and the certainty of the evidence was evaluated with the GRADE approach. Results Of 6450 studies screened, we identified 21 observational studies of Nanostim and Micra leadless pacemakers. The pooled incidence of complications of leadless versus traditional pacemakers at 1, 6, 12-24 months show the odds are clinically and statistically different (OR=0.66, 95% CI: 0.42–1.02; OR=0.44, 95% CI: 0.22–0.86; OR=0.41, 95% CI: 0.32–0.53 respectively). The pooled incidence of infection rate at 6, 12-24 months is lower in patients with LP (OR=0.37, 95% CI: 0.31–0.44; OR=0.20, 95% CI: 0.00–97.31). The studies comparing all-cause mortality during 6, 12-24 months in leadless versus traditional pacemakers did not show statistically significant differences in these outcomes (OR=1.26, 95% CI: 0.88–1.81; OR=0.86, 95% CI: 0.25–2.92 respectively. Conclusion Our results show that complications and infections occur less frequently in patients with leadless pacemakers than in patients with conventional pacemakers with no difference in all-cause mortality. However, there is a need for high-quality randomized clinical trials and propensity score-matched studies focusing on this clinically relevant question.Complication Forest plotsInfection Forest plots

The importance of heart rate on left ventricular global longitudinal strain in echocardiography: novel insights facilitated by automated deep learning methods

Abstract Background Heart rate (HR) is assumed to influence echocardiographic measurements. Consequently, HR needs to be considered for accurate assessment of cardiac function. Despite left ventricular global longitudinal strain (LV GLS) being recognised as a valuable measure of cardiac function, its normal reference ranges remain confined to patients within a limited range of resting HR. So far, time-consuming manual analyses and high measurement variability have precluded comprehensive assessment of the interplay between HR and LV GLS. Using fully automated GLS measurements provided by novel deep learning (DL) methods, it is now possible to evaluate changes in LV GLS across a wide range of HR. Purpose To improve echocardiographic assessments across a wide range of HR intervals, we aimed to study the influence of controlled HR variations on LV GLS using programmable pacemakers and fully automated DL measurements. Methods Participants with sinus node dysfunction and implanted programmable pacemakers were enrolled. Echocardiographic acquisitions were obtained at baseline HR and during stepwise increments by 10 beats/min, targeting a range from 50 to 140 beats/min. Recordings of cine-loops including 10 cardiac cycles were obtained for the four-chamber, two-chamber, and apical long axis view. LV GLS was measured for all cycles using a fully automated DL method developed by our group, and presented as mean of the three standard apical views for all patients at each HR level. A linear mixed model was used for construction of an overall trendline based on the estimated fixed effects across all 50 patients, stating patient number as the random effect. The correlation between HR and LV GLS was evaluated by a likelihood ratio test. Results Fifty patients were included, 52% females, mean age 68 years (27 to 88 years). All patients had preserved atrioventricular conduction. Resting HR ranged from 50 to 87 beats/min (mean 64 beats/min). At baseline echocardiographic acquisition, most participants were within normal ranges for LV volumes, systolic and diastolic function. A total of about 13,000 cardiac cycles were automatically analysed by the DL method. The overall trend demonstrated a linear relation between increasing HR and decreasing absolute LV GLS (Figure 1). Across HR increments from 50 to 140 beats/min, there was a 32% (22%–42%) reduction in absolute LV GLS, declining from -17.1% to -11.7%. The strong correlation between changes in HR and LV GLS was further supported by a highly significant likelihood ratio test (p-value <0.001). Conclusions There was a reduction of absolute LV GLS with increasing HR. These findings emphasize the importance of integrating HR considerations into clinical echocardiography practice. Moreover, the results highlight that DL methods can unlock substantially richer insights from individual patient data, offering a new pathway towards more personalized and precise cardiac diagnostics.Figure 1

Arrhythmias in adult patients after Rastelli surgery: a single-centre experience.

Rastelli surgery is used for the correction of several CHDs. Although late-onset cardiac arrhythmias have emerged as a major complication after corrective surgeries, there is a paucity of data on arrhythmias after Rastelli surgery. This retrospective cohort study was conducted on patients who had undergone Rastelli surgery and have been followed at the adult CHD clinic at our hospital. A total of 55 patients (36.4% female, age 22.2 ± 6.4 years) were followed for a median period of 24.2 (20.6-31.0) years. Tachyarrhythmias occurred in 21 (38.4 %) patients (n = 15 for atrial tachycardia, 5 for ventricular tachycardia, and 1 for both atrial and ventricular tachycardia). Older age at surgery was significantly associated with the risk of tachyarrhythmias (P = 0.022). Bradyarrhythmia occurred in 12 (21.8%) patients and consisted of perioperative AV block (n = 5), late AV block (n = 1), and sinus node dysfunction (n = 6). Nine (16.4%) patients underwent catheter ablation. The mechanisms of atrial arrhythmias include cavotricuspid isthmus-dependent and surgical scar-dependent intra-atrial reentrant tachycardias. Among the three patients who underwent ablation for ventricular tachycardia, all circuits were dependent on the scar at the base of the right ventricle to pulmonary artery conduit. Median survival free from any event (arrhythmia, death, or heart failure) was 31.6 (28.1-35.1) years after Rastelli surgery. The prevalence of arrhythmias late after Rastelli surgery is substantial and increases in the second decade after surgery. Older age at surgery is associated with a higher prevalence of arrhythmias.

Outcomes of the Modified Warden Procedure for Partial Anomalous Pulmonary Venous Connection Drainage to a High Location in the Superior Vena Cava

To report the safety and effectiveness of a modified Warden procedure. Twenty-six (26) patients underwent modified Warden surgery at our centre from September 2017 to September 2021. In all patients, the superior vena cava (SVC) was reconstructed by turning the atrial wall in the main body of the right atrium upwards and applying fresh autologous pericardial patches. There were 13 male patients and 13 female patients, and the median age of the patients was 7.0 (range, 0.3-47.0) years. The median follow-up time after surgery was 47.0 (range, 32.0-80.0) months. The aortic cross-clamp time was 108.50±34.72 minutes, the cardiopulmonary bypass time was 154.81±41.65 minutes, the median postoperative mechanical ventilation time was 8.5 (range, 0.0-91.0) hours, the median intensive care unit stay was 43.5 (range, 15.0-352.0) hours, and the median length of postoperative hospital stay was 7.0 (range, 6.0-19.0) days. All patients were safely and successfully discharged from the hospital. No deaths or sinus node dysfunction occurred during the follow-up period. The mean gradient of the reconstructed SVC and/or the right pulmonary vein (PV) increased in eight patients and decreased to less than 1 mmHg in six patients. One (1) adult patient had already undergone two vascular interventions, and one child had persistent stenosis but did not undergo reoperation at the time of the study. In addition, two patients were subjected to pericardial windowing. A modified Warden technique using a right atrial flap and autologous pericardium effectively corrected the high-plane connection between the PVs and SVC. This technique effectively avoids sinus node dysfunction; however, a short-term increase in the differential pressure of the re-established SVC or PV after the procedure is acceptable, and reintervention is required only in rare cases.

Genetic basis and causal relationship between atrial fibrillation and sinus node dysfunction: Evidence from comprehensive genetic analysis

BackgroundAtrial fibrillation (AF) and sinus node dysfunction (SND) are commonly observed together clinically. However, little is known about the genetic background and causal relationship between the two. MethodsFirstly, we investigated the global and local genetic correlations between AF and SND using LDSC and HESS. Then, we identified shared “Novel SNPs” between AF and SND through two complementary cross-trait meta-analyses and mapped the “pleiotropic genes” behind these SNPs, validated by colocalization analysis. Additionally, we explored the degree of genetic enrichment of SNPs in specific tissues using LDSC-SEG and MAGMA, and identified potential functional genes in tissues using summary data-based Mendelian randomization (SMR). Finally, two-sample Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) were used to explore the causal relationship between AF and SND. ResultsBoth global and local genetic correlation analyses revealed a high positive genetic correlation between AF and SND. HESS identified 9 shared loci, with chr4(q25-q26) and chr11(p11.12-q11) being prominent. Cross-trait meta-analysis and colocalization analysis identified ENPEP and PITX2 as novel pleiotropic genes. MAGMA revealed genetic enrichment of SNPs for AF and SND in the “Heart Left Ventricle” and “Heart Atrial Appendage” tissues, with CEP68 and BEST3 identified as potential functional genes through SMR. MR analysis indicated that AF increases the risk of SND, even after adjusting for confounding factors. ConclusionThis study provides genetic evidence for the increased risk of SND associated with AF, identifying multiple shared risk loci and enriched tissues, and discovering 2 novel pleiotropic genes and 2 new functional genes.

7068 Paraganglioma in Cyanotic Congenital Heart Disease

Abstract Disclosure: R. Lis: None. V. Hamidi: None. Paragangliomas arise from the non-chromaffin cells of the parasympathetic nervous system, which are composed of glomus cells. These function as chemoreceptors in response to hypoxia. Carotid body paragangliomas have been linked to conditions with chronic hypoxia. This was first seen in residents of high altitude locations in a case report presented by Saldana et. al and regression of a paraganglioma with resolution of hypoxia was reported by Gruber et. al. There have been few additional case reports of Paraganglioma in other hypoxic states. We present a rare case of a functional Paraganglioma in a patient with Cyanotic Congenital Heart Disease (CCHD).This is a 19 year old female with a history of CCHD due to double inlet left ventricle and transposition of the great arteries. Soon after birth, she had a fontan procedure. She subsequently developed fontan associated liver disease as well as chronic kidney disease, hypertension, sinus node dysfunction, and complete heart block. Her baseline oxygen saturation was 78-85%. Her heart rate was 40-49 beats per minute with upcoming plans for pacemaker placement. Her blood pressure ranged 90/50 to 150/80 mmHg on Amlodipine 5 mg and Lisinopril 2.5 mg. She routinely received abdominal imaging to monitor her liver disease. A liver MRI incidentally revealed a retroperitoneal mass concerning for a paraganglioma. Serum Normetanephrines were found to be 26.60 nmol/L (reference range less than 0.89). 24 hr Urine Norepinephrine was 1,187 ug/d (reference range 14-20). Further imaging was negative for additional sites of disease. Given her complete heart block, she was started on alpha blockade only prior to pacemaker placement. After the pacemaker was placed, she was started on beta blockade and underwent surgical resection of her paraganglioma. The pathology confirmed paraganglioma and mutation testing was negative for germline mutations including SDH, VHL, RET, NF1 mutations. Paragangliomas in patients with CCHD have been scarcely described in the literature given the rarity of both of these conditions. However, there is a relatively increased incidence of paragangliomas in the CCHD population due to chronic hypoxia triggering the hypoxia pathway. EPAS1 mutated HIF2alpha is often found to be the culprit in these patients. In addition, case reports have often described these patients to either be asymptomatic or have potential symptoms masked by their cardiac disease. Therefore, CCHD patients are at increased risk for paragangliomas and warrant additional awareness and regular screening. Screening has been proposed to start after 10 years of hypoxia in a case review by Agarwal et. al. as paraganglioma incidence in CCHD populations has not been seen before age 11. Incidence of recurrence is not yet widely studied, but significant concern for recurrence is warranted if the etiology of hypoxia is not reversed. Presentation: 6/3/2024

A single-center outcome of choosing catheter ablation as the initial treatment in tachycardia–bradycardia syndrome and a new predictive factor for pacemaker implantation

BackgroundThe relationship between sinus node dysfunction and atrial fibrillation (AF) has been well known. The reversibility of sinus node dysfunction is indeed a critical factor in determining the treatment strategy in patients with tachycardia–bradycardia syndrome (TBS). We aimed to assess the clinical outcome of choosing catheter ablation as the initial treatment in tachycardia–bradycardia syndrome and predictive factors leading to the implantation of a permanent pacemaker (PPM) in these patients.MethodsPatients with TBS who had been taken AF catheter ablation from 2012 to 2021 were reviewed, and 113 patients were enrolled. Patients were divided into two groups based on whether a “sinus pause episode of more than 3 s unrelated to tachyarrhythmia” coexists (Group I, n = 20) or not (Group II, n = 93).ResultsCompared to Group II, baseline characteristics showed that Group I was comprised of more female gender (p = 0.043), with hypertension (p = 0.033), and with enlarged left atrium (p = 0.003). An average three-year follow-up found that eight patients (8/113, 7%) were implanted PPM (5/20, 25% in Group I vs. 3/93, 3.2% in Group II, p = 0.001). Using a multivariate model, a “sinus pause episode unrelated to tachyarrhythmia” was strongly associated with PPM implantation after catheter ablation in patients with TBS (HR 6.765, 95% CI 1.355–33.763, p = 0.020). Only four out of 113 patients (3.5%) progressed to persistent or permanent AF.ConclusionsAfter catheter ablation as the initial treatment in TBS, only 7% underwent PPM implantation, and an isolated sinus pause was a predictive factor for requiring PPM implantation. In addition, even in patients who undergo catheter ablation with subsequent PPM implantation, we can expect to improve the clinical outcome associated with a reduced AF burden.

Predictors of Clinical Success of Cardioneuroablation in Patients WithSyncope: Results of a Multicenter Study.

Cardioneuroablation (CNA) is a promising treatment for syncope. This study sought to analyze the success and risk of CNA ,and to describe predictive factors of CNA success in patients with syncope. Seventy-seven consecutive patients with syncope treated with CNA in 22 hospitals and at least 6months of follow-up were included. Patients with reflex cardioinhibitory, mixed syncope, functional sinus node dysfunction (SND), or functional atrioventricular block were included. The primary endpoint was the recurrence of syncope after the CNA. Mean age was 49.3 ± 13.4 years and 54.5% were women. Five (6.5%) patients presented complications. Three patients presented SND, 1 required a pacemaker. During a median follow-up of 12months (Q1-Q3: 8-20months), 26 (33.8%) patients had recurrence of syncope. Women had a significantly higher risk of recurrence compared with men (HR: 3.3; 95% CI: 1.2-8.8; P=0.016). Patients >50 years of age had a significantly lower risk of recurrence compared with younger patients (HR: 0.3; 95%CI: 0.1-0.9; P=0.032). The risk of recurrence in mixed syncope was significantly higher than in cardioinhibitory syncope (HR: 4.4; 95%CI: 1.1-17.5; P=0.033). Syncope recurrence was significantly less frequent in patients treated with general anesthesia or deep sedation compared with conscious sedation (HR: 0.2; 95%CI: 0.1-0.6; P=0.002). Finally, the number of radiofrequency applications (≤30 or >30) had a significant association with CNA success (HR: 0.4; 95%CI: 0.2-0.9; P=0.042). These results were adjusted for confounding factors. In this multicenter study, the effectiveness of CNA was less than previously reported. We found a 3.9% risk of SND. Male sex, age >50 years, cardioinhibitory syncope, general anesthesia or deep sedation, and >30 radiofrequency applications could predict success of CNA for syncope.

Chronic Wireless Communication Between Dual-Chamber Leadless Pacemaker Devices

BackgroundAveir™ DR (Abbott) is a dual-chamber leadless pacemaker (LP) system with distinct atrial and ventricular LPs (ALP, VLP) that communicate wirelessly to deliver atrioventricular synchronous pacing. Success rates of these implant-to-implant (i2i™) transmissions have not been systematically evaluated. ObjectiveTo evaluate chronic i2i success rates in a clinical setting. MethodsPatients meeting standard dual-chamber pacing indications were enrolled and implanted with dual-chamber LP systems as part of a prospective, international clinical trial (“Aveir DR i2i Study”). The percent of successful i2i transmissions from ALP-to-VLP (A-to-V) and VLP-to-ALP (V-to-A) were interrogated from LPs in de novo patients using the device programmer at implant, discharge, and at 1-, 3-, and 6-months post-implant (1M, 3M, 6M). Results399 patients completed device implant and i2i diagnostic interrogation (62% male; age 69 years; 65% sinus node dysfunction, 32% AV block). Median A-to-V and V-to-A i2i success rates exceeded 90% of beats at all time-points from implant to 6M. The minority of patients with A-to-V or V-to-A i2i success in <70% of beats at implant (A-to-V: 19% of patients, V-to-A: 31% of patients) showed roughly 40% improvement by 1M, with this minority dropping to roughly 5% of patients by 6M. Improvement in i2i communication success may be attributed to reprogramming of i2i setting levels, natural changes in dominant posture, and device stabilization. ConclusionWireless implant-to-implant communication in the new dual-chamber leadless pacemaker system demonstrated successful transmissions in >90% of beats throughout the 6-month evaluation period. Communication success improved significantly over time post-implant for specific subgroups.

Editorial: Is There a Relationship/An Association Between ABO Blood Group System and Cardiac Conduction Disorders?

Abstract Introduction Data from the literature suggest a slight increase in cardiovascular risk for people with non-O blood types. The purpose of the study was to evaluate if there is an association between advanced cardiac conduction disorders and blood groups. Material and methods In this retrospective study, a group of patients with atrio-ventricular conduction disorders or sinus node disease, having an indication for permanent cardiostimulation, was analyzed and compared with a control group consisting of patients who underwent coronary angiography or elective peripheral angiography. The blood group was determined in all patients. Univariate and multivariate statistical methods were used. Results Six hundred forty patients, mean age 72±11y, 55.3% men, were included: 320 patients with advanced atrio-ventricular conduction disorders or sinus node dysfunction in the study group and 320 patients in the control group. Blood type A had the highest prevalence (46.8%), followed by blood types O (28.95%), B (16.74%) and AB (7.51%). In the group with heart rhythm disorders, patients with blood type A had an increased risk of atrio-ventricular block (OR 1.38, p= 0.02), but not with sinus node disease (OR 1.02, p= 0.98). Blood type O had a protective role both for atrio-ventricular block and for sinus node dysfunction (OR 0.65, p= 0.01). Conclusion Blood type A proved to be an independent predictor for atrio-ventricular conduction disorders in patients with severe heart rhythm disorders with indication for permanent cardiostimulation.

Paradoxical cerebral embolism three decades after mustard surgery in a patient with complete transposition of the great arteries: a case report.

Atrial switch procedures such as the Mustard operation were previously popular for the complete transposition of the great arteries (i.e. dextro-transposition of the great arteries [d-TGA]). Patients with d-TGA who underwent atrial switch procedures approximately three decades ago have now entered adulthood. A female patient in her 30s with d-TGA had a paradoxical embolic stroke following the initiation of a low-dose oestrogen plus progesterone oral pill for dysmenorrhoea. She underwent Mustard surgery when she was 2 years old. Following a series of procedures including implantation of a permanent pacemaker that was required because of sinus node dysfunction, she had reached adulthood, was living by herself and working independently. One month after taking the low-dose oestrogen plus progesterone oral pill, venous thrombosis occurred in the left soleus and left peroneal veins; and she experienced an acute ischaemic stroke in the right middle cerebral artery area. Transoesophageal echocardiography revealed that the shunt was present only during the Valsalva manoeuvre. Based on the examinations, the patient was diagnosed with juvenile ischaemic stroke as a result of a paradoxical embolism. These findings suggest that paradoxical cerebral embolism can occur as a late complication in patients with d-TGA who underwent the Mustard operation as children.

Sigmoidal heart rate response pattern during exercise in patients with chronic heart failure.

Detailed heart rate (HR) response patterns during exercise in patients with heart failure (HF) and sinus rhythm remain uncertain. We screened consecutive patients with HF who underwent cardiopulmonary exercise tests at a large academic center from November 2013 to July 2023. HR response during exercise was statistically classified using logistic differential equation models. A total of 99 patients were included. Of them, 75 patients were assigned to "sigmoidal pattern" and the other 24 to "exponential pattern." Patients with the sigmoidal pattern were older and exhibited higher plasma B-type natriuretic peptide levels. Increases in HR and oxygen consumption (V̇o2)/kg up to the anaerobic threshold level were not different between both patterns. However, beyond the threshold, the sigmoidal pattern group showed no further increase in HR and significantly lower V̇o2/kg than their counterparts (interactions for P < 0.001). HR response during exercise in patients with heart failure and sinus rhythm was categorized into two unique groups: sigmoidal and exponential patterns. More detailed clarification of the sigmoidal pattern, potentially indicating sinus node dysfunction, should offer new clinical insights for chronotropic incompetence.NEW & NOTEWORTHY Heart rate response patterns can be classified into two groups among patients with chronic heart failure reaching maximal exertion: sigmoidal and exponential.

Children and Adolescent Patients with Variants in the ATP1A3 -encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate an Impaired QT Response to Bradycardia and Predisposition to Sinus Node Dysfunction.

Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition. We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 - related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed. The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 - related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds. Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contribute to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction. What is Known: Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia. What the Study Adds: The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

Role of new generation implantable loop recorders in managing undiagnosed pediatric cardiac symptoms

Pediatric cardiac symptoms such as palpitations, syncope, or seizure-like episodes pose diagnostic challenges for general pediatricians. These symptoms, though often benign, may reveal underlying arrhythmias or inherited cardiac conditions (ICCs), affecting the quality of life and limiting activity participation. The purpose of this study is to determine the effectiveness and safety of implantable loop recorders (ILRs) in diagnosing and managing arrhythmias in pediatric patients. A retrospective cohort study conducted over an 8-year period from January 2016 to December 2023 in a single pediatric cardiology center. A cohort of 155 pediatric patients (median age 11.4 years) who underwent ILR implantation were selected based on symptoms such as palpitations, chest pain, or syncope, and those with previously recorded arrhythmias or high-risk ICCs. The primary outcomes were the diagnostic yield of ILRs for arrhythmias and subsequent changes in patient management. Diagnostic yield was defined as the detection of relevant arrhythmias, such as pauses of 3 s or longer, high-degree AV block, sinus node dysfunction, supraventricular tachycardia, ventricular tachycardia, or inappropriate sinus tachycardia. The median follow-up period was 2.3 years (845 days). Diagnostic arrhythmias were recorded in 60% of patients with symptom-activated transmissions and 80% of device-activated transmissions. Sinus pauses (37.5%) and VT (30%) were the most common arrhythmias detected. In patients with syncope (n = 76), 30% had relevant arrhythmias. In the palpitations group (n = 20), 35% had relevant arrhythmias. Approximately 80% of patients with ILR-diagnosed arrhythmias underwent targeted management, including medication changes and additional procedures. No significant complications were observed; minor complications occurred in 2.5% of patients.Conclusions: New generation ILRs are effective and safe for diagnosing and managing pediatric arrhythmias, providing significant reassurance to patients and families. Further studies are needed to evaluate the impact of ILRs on quality of life and sports participation in high-risk young patients.What is Known:• Pediatric Cardiac Symptoms: Symptoms like palpitations, syncope, and seizure-like episodes in pediatric patients pose significant diagnostic challenges.• Diagnostic Tools: Traditional diagnostic tools such as ECG, Holter monitors, and external loop recorders often have low diagnostic yields due to the sporadic nature of symptoms.• Implantable Loop Recorders (ILRs): ILRs have been shown to improve the diagnostic yield for arrhythmias in adults and provide long-term rhythm monitoring.What is New:• Effectiveness in Pediatrics: This study demonstrates that new generation ILRs significantly enhance the diagnostic yield for arrhythmias in pediatric patients with undiagnosed cardiac symptoms.• Safety and Efficacy: The study confirms that ILRs are both safe and effective in the pediatric population, with minimal complications and high diagnostic accuracy.• Targeted Management: Findings show that ILR-diagnosed arrhythmias lead to targeted management changes in approximately 80% of cases, including medication adjustments and additional procedures.• Long-term Monitoring: ILRs provide continuous long-term monitoring, offering reassurance to patients and families, and potentially improving quality of life and participation in activities for high-risk young patients.

Abstract Mo062: Cpne5 is Necessary for Normal Sinoatrial Node Function

Background: Cpne5 (Copine 5) is a Ca2+-dependent phospholipid binding protein implicated in membrane trafficking but has no known role within the heart to date. In single-cell RNA-sequencing (scRNA-seq) of the developing mouse heart, we found Cpne5 gene expression to be highly enriched throughout the cardiac conduction system (CCS). Further, variants in CPNE5 were identified in 6 independent GWAS related to heart rate variability in humans. We therefore hypothesize that Cpne5 is necessary for normal CCS function. Objective: Determine whether Cpne5 is necessary for the normal development and/or function of the CCS. Methods: To assess the necessity of Cpne5, homozygous systemic knockout (KO) mice were generated using CRISPR/Cas9. Cpne5KO and littermate wild-type (WT) control mice were characterized using surface electrocardiogram (ECG), continuous telemetry and echocardiogram. Protein expression of Cpne5 and CCS-related ion channels were assessed by immunofluorescence of tissue sections, isolated adult murine SAN cells and whole mount immunostaining with 3D volumetric imaging (iDISCO+). Further, CRISPR-mediated deletion of CPNE5 was performed in human induced pluripotent stem cells (hiPSC). Differentiated SAN-like cells were phenotyped via calcium transient (CaT) dynamics and microelectrode array. Results: Successful deletion of Cpne5 in CRISPR-generated KO mice was confirmed by PCR immunofluorescence. Homozygous Cpne5KO mice were viable, showed normal growth and allele frequencies segregated in a normal Mendelian fashion. No gross anatomic defects of the CCS were observed in Cpne5KO mice and transthoracic echocardiogram studies showed slight reduction in left ventricular fractional shortening but otherwise a structurally normal heart. Notably, while surface electrocardiogram (ECG) demonstrated normal intervals (PR, QRS, QTc), Cpne5KO mice exhibited pronounced sinus arrhythmia, sinus pauses, and increased heart rate variability compared to WT controls on long term telemetry. Additionally, CPNE5KO hiPSC-derived SAN-like cells exhibited irregular CaT as well as significant beat period variability compared to isogenic WT controls. Conclusion: Systemic loss-of-function of Cpne5 in mice resulted in sinus node dysfunction, consistent with an hiPSC-derived SAN model and human GWAS data, implicating a novel, cell-intrinsic role for Cpne5 in CCS function and/or development. Additional phenotyping and molecular studies are ongoing to further elucidate the underlying mechanism.

Abstract We042: Gelatin hydrogel elasticity influences TBX18-induced pacemaker cell behavior

Introduction: Extracellular matrix (ECM) stiffness plays a role in determining cell behavior during development and maintenance of organ function. Polystyrene dishes typically show an elastic modulus of 1 gigaPa, which is far from the elastic modulus of 10 to 15 kiloPa for myocardium. Gelatin, a derivative of collagen, is a major structural scaffolding in the myocardium including the sinoatrial node. Hypothesis: We hypothesized that gelatin hydrogel at varying stiffness serves as a platform to modulate the automaticity of cardiac pacemaker cells. Methods: Freshly isolated neonatal rat ventricular myocytes (NRVMs) were cultured as monolayers on regular, plastic cell culture plate or on 3%, 5%, and 10% gelatin hydrogel that represents a stiffness of 1.3 ± 0.3, 6.4 ± 1.5, and 13.6 ± 3.5 kPa, respectively. All cell culture surface was coated with fibronectin. NRVMs were transduced with Adv-TBX18 or Adv-GFP at day 0 (d0). Results: TBX18-NRVMs showed significantly more spontaneous synchronous contractions on the gelatin hydrogel (22 ± 12, 29 ± 1, 33 ± 9 on 3, 5, or 10% gelatin, respectively) than on plastic (10 ± 11) at d4. Control, GFP-NRVMs showed few spontaneous synchronous contractions regardless of the cell culture platform (3 ± 4, 2 ± 3, 0 ± 0 bpm at 3, 5, 10% gelatin, respectively; 3 ± 7 bpm on plastic, n = 5 to 6 wells/group) at d4. TBX18-NRVMs exhibited significantly more spontaneous synchronous Ca 2+ transients/min on 10% gelatin hydrogel (33 ± 2) than on 3% gelatin hydrogel (9 ± 2) or 5% gelatin hydrogel (19 ± 8) (n = 3, p&lt;0.05) at d8. Immunostaining revealed that Hcn4 protein expression in TBX18-NRVMs was higher on 10% gelatin than on plastic at d2. The percentage of vimentin+ nonmyocytes in TBX18-NRVMs was higher on 10% gelatin (39.5 ± 2.2 %) compared to either on 5% (26.6 ± 1.7%) or on 3% gelatin (27.5 ± 4.2) at d6. Conclusions: Our data indicate that spontaneous and synchronized contractions of TBX18-induced pacemaker cells were significantly higher on gelatin hydrogel with myocardium-like stiffness compared to those grown on plastic culture medium. The data suggest that modulating ECM stiffness may impact the automaticity of cardiac pacemaker tissues, and could serve as a platform to study sinus node dysfunction.