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Background: The 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. Methods: Patients 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). Results: Compared 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. Conclusions: After 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. [ABSTRACT FROM AUTHOR]

Implantable loop recorders (ILRs) are increasingly used to evaluate patients with unexplained syncope. Identification of all predictors of bradycardic syncope and consequent permanent pacemaker (PPM) insertion is of substantial clinical interest as patients in the highest risk category may benefit from upfront pacemaker insertion. We performed a systematic review and meta-analysis to identify risk predictors for PPM insertion in ILR recipients with unexplained syncope. An electronic database search (MEDLINE, Embase, Scopus, Cochrane) was performed in June 2023. Studies evaluating ILR recipients with unexplained syncope and recording risk factors for eventual PPM insertion were included. A random effects model was used to calculate the pooled odds ratio (OR) for clinical and electrocardiographic characteristics with respect to future PPM requirement. Eight studies evaluating 1007 ILR recipients were included; 268 patients (26.6%) underwent PPM insertion during study follow-up. PPM recipients were older (mean age, 70.2 ± 15.4 years vs 61.6 ± 19.7 years; P <.001). PR prolongation on baseline electrocardiography was a significant predictor of PPM requirement (pooled OR, 2.91; 95% confidence interval, 1.63–5.20). The presence of distal conduction system disease, encompassing any bundle branch or fascicular block, yielded a pooled OR of 2.88 for PPM insertion (95% confidence interval, 1.53–5.41). Injurious syncope and lack of syncopal prodrome were not significant predictors of PPM insertion. Sinus node dysfunction accounted for 62% of PPM insertions, whereas atrioventricular block accounted for 26%. Approximately one-quarter of ILR recipients for unexplained syncope require eventual PPM insertion. Advancing age, PR prolongation, and distal conduction disease are the strongest predictors for PPM requirement. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background There is limited research on the intra‐individual efficacy of ventricular pacing minimization algorithms developed by Biotronik—the Ventricular Pace Suppression algorithm (VpS) and the Intrinsic Rhythm Support plus algorithm (IRSplus) (BIOTRONIK SE & Co. KG, Berlin, Germany). We performed a randomized pilot trial that evaluated the efficacy of two algorithms in patients with symptomatic sinus node dysfunction (SND) who received a dual‐chamber pacemaker. Methods The trial was conducted in 11 tertiary hospitals in South Korea. The patients were randomized to either the VpS or IRSplus algorithm group after a 3‐month period of fixed atrioventricular (AV) delay. The primary outcome was the ventricular pacing percentage (Vp%) at each follow‐up visit. The secondary outcomes were the occurrence of heart failure (HF) and atrial fibrillation (AF) during the study period. Results Data from 131 patients were analyzed. Initially, their average Vp% over 3 months with a fixed AV interval was 14.1 ± 19.4%. Patients were randomly assigned to VpS and IRSplus groups, with 66 and 65 in each. Algorithms reduced average Vp% to 4.0 ± 11.3% at 9 months and 6.7 ± 14.9% at 15 months. These algorithms were more effective for patients with paced AV delay (PAVD) ≤300 ms compared to those with PAVD >300 ms. Both algorithms were equally effective in reducing Vp%. Clinical AF or HF hospitalization was not observed during the study period. Conclusion The VpS and IRSplus algorithms are effective and safe in minimizing unnecessary ventricular pacing in patients with SND.

Background: There is limited research on the intra‐individual efficacy of ventricular pacing minimization algorithms developed by Biotronik—the Ventricular Pace Suppression algorithm (VpS) and the Intrinsic Rhythm Support plus algorithm (IRSplus) (BIOTRONIK SE & Co. KG, Berlin, Germany). We performed a randomized pilot trial that evaluated the efficacy of two algorithms in patients with symptomatic sinus node dysfunction (SND) who received a dual‐chamber pacemaker. Methods: The trial was conducted in 11 tertiary hospitals in South Korea. The patients were randomized to either the VpS or IRSplus algorithm group after a 3‐month period of fixed atrioventricular (AV) delay. The primary outcome was the ventricular pacing percentage (Vp%) at each follow‐up visit. The secondary outcomes were the occurrence of heart failure (HF) and atrial fibrillation (AF) during the study period. Results: Data from 131 patients were analyzed. Initially, their average Vp% over 3 months with a fixed AV interval was 14.1 ± 19.4%. Patients were randomly assigned to VpS and IRSplus groups, with 66 and 65 in each. Algorithms reduced average Vp% to 4.0 ± 11.3% at 9 months and 6.7 ± 14.9% at 15 months. These algorithms were more effective for patients with paced AV delay (PAVD) ≤300 ms compared to those with PAVD >300 ms. Both algorithms were equally effective in reducing Vp%. Clinical AF or HF hospitalization was not observed during the study period. Conclusion: The VpS and IRSplus algorithms are effective and safe in minimizing unnecessary ventricular pacing in patients with SND. [ABSTRACT FROM AUTHOR]

Aims Physiological activation of the heart using algorithms to minimize right ventricular pacing (RVPm) may be an effective strategy to reduce adverse events in patients requiring anti-bradycardia therapies. This systematic review and meta-analysis aimed to evaluate current evidence on clinical outcomes for patients treated with RVPm algorithms compared to dual-chamber pacing (DDD). Methods and results We conducted a systematic search of the PubMed database. The predefined endpoints were the occurrence of persistent/permanent atrial fibrillation (PerAF), cardiovascular (CV) hospitalization, all-cause death, and adverse symptoms. We also aimed to explore the differential effects of algorithms in studies enrolling a high percentage of atrioventricular block (AVB) patients. Eight studies (7229 patients) were included in the analysis. Compared to DDD pacing, patients using RVPm algorithms showed a lower risk of PerAF [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.57–0.97] and CV hospitalization (OR 0.77, 95% CI 0.61–0.97). No significant difference was found for all-cause death (OR 1.01, 95% CI 0.78–1.30) or adverse symptoms (OR 1.03, 95% CI 0.81–1.29). No significant interaction was found between the use of the RVPm strategy and studies enrolling a high percentage of AVB patients. The pooled mean RVP percentage for RVPm algorithms was 7.96% (95% CI 3.13–20.25), as compared with 45.11% (95% CI 26.64–76.38) of DDD pacing. Conclusion Algorithms for RVPm may be effective in reducing the risk of PerAF and CV hospitalization in patients requiring anti-bradycardia therapies, without an increased risk of adverse symptoms. These results are also consistent for studies enrolling a high percentage of AVB patients. [ABSTRACT FROM AUTHOR]

Introduction: This study was undertaken to explore the potential therapeutic effects of Tongyang Huoxue Granules (TYHX) on sinoatrial node (SAN) dysfunction, a cardiac disorder characterized by impaired impulse generation or conduction. The research question addressed whether TYHX could positively influence SAN ion channel function, specifically targeting the sodium-calcium exchanger (INCX) and L-type calcium channel (ICaL) of the SAN. Methods: Sinoatrial node cells (SANCs) were isolated and cultured from neonatal Japanese big-eared white rabbits within 24 h of birth. The study encompassed five groups: Control, H/R (hypoxia/reoxygenation), H/R+100 μg/mL TYHX, H/R+200 μg/mL TYHX, and H/R+400 μg/mL TYHX. The H/R model, simulating hypoxia/reoxygenation stress, was induced within 5 days of culture. Whole-cell patch clamp technique was employed to record currents following a 3-min perfusion and stabilization period with TYHX. Results: TYHX administration demonstrated improvements in the ignition phase of impaired SANCs. The half-maximal effective dose of TYHX, as determined by SANC beating frequency, was found to be 323.63 μg/mL. Inward current density of INCX increased in response to TYHX (200 and 400 μg/mL), while TYHX enhanced ICaL current density in H/R SANCs, with 400 μg/mL exhibiting greater efficacy. Additionally, TYHX regulated the gating mechanisms of ICaL by right-shifting the steady-state inactivation curve and accelerating recovery from inactivation. Notably, TYHX increased the activation time constant under 200 and 400 μg/mL, prolonged the fast inactivation time constant t1 with 400 μg/mL, and extended the slow inactivation time constant t2 with 100 and 400 μg/mL. Discussion and conclusion: The findings suggest that TYHX may hold promise as a therapeutic intervention for sinus node dysfunction, offering potential avenues for drug development aimed at safeguarding SAN function. [ABSTRACT FROM AUTHOR]

ObjectiveNon-ischemic symptomatic reversible bradyarrhythmia is a poorly characterized yet common clinical challenge. This study aimed to assess the incidence and predictors of recurrence and the need for permanent cardiac pacing in patients with non-ischemic symptomatic reversible bradyarrhythmia.MethodsThis prospective single-center study enrolled 124 consecutive adult patients with non-ischemic symptomatic reversible bradyarrhythmia who were followed up for up to 24 months after conservative management during index hospitalization. The primary endpoint was a recurrence of bradyarrhythmia requiring permanent cardiac pacing. The secondary endpoint was a composite of recurrence requiring permanent pacing, readmission, or death. Univariate and multivariate analyses were conducted to determine the predictors of the endpoints.ResultsSinus node and atrioventricular node diseases were seen in 66.1% and 33.9% of patients, respectively. The most common causes of bradyarrhythmia were negative chronotropic drugs (58.1%) and hyperkalemia (55.6%). Permanent pacing was required in 21.8% of patients after a recurrence. Advanced atrioventricular block at presentation (HR: 6.10, 95% CI: 2.45–15.20, p

Aims In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND. Methods and results We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND. Conclusion Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure. [ABSTRACT FROM AUTHOR]

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IntroductionLithium is a well-known agent to cause systemic toxicity with its narrow therapeutic window. Toxic cardiac effects are known but seldomly reported and can manifest as sinus node dysfunction (SND) ranging from delayed conduction to sinus arrest with the potential to induce asystole. Theophylline a positive chronotropic agent has been previously used for correction of sinus node dysfunction but never been utilized for the correction of lithium-induced SND. We report the first successful use of Theophylline for rate/rhythm correction of SND in a patient presenting with acute lithium toxicity along with a review summarizing the clinical features of all published literature regarding lithium-induced SND.MethodsCase report and systematic review of the literature are presented. Three independent scientific databases were queried for reports of lithium-induced SND. A clinical compendium was then generated detailing associated clinical data and descriptive statistics were performed.Results1,117 reports were initially retrieved with full-text review yielding a cohort of 49 unique, independent studies. (61.4%) of patients presented with a supratherapeutic lithium level, 12 (21.1%) were normotherapeutic, and 11 (19.3%) were subtherapeutic. EKG findings varied but most commonly described sinus node dysfunction with a variable degree of sinoatrial block with sinus bradycardia (54.39%) and sinus arrest (29.82%) predominating. Twelve patients (21.1%) required inotrope or vasopressor support. 10 (17.5%) of patient required temporary pacing while 7 (12.3%) required permanent pacemaker implantation. In the majority of cases no significant permanent sequelae were reported as 50 (87.7%) patients recovered, 2 (3.5%) patients had persistent sinus node dysfunction, and 2 (3.5%) patients expired as a result of acute lithium toxicity.Discussion & conclusionIn this review we report the most up-to-date and comprehensive clinical compendium of lithium-associated sinus node dysfunction along with describing a novel treatment methodology to rapidly correct lithium-induced cardiac toxicity in a patient with long-standing bipolar disorder on chronic lithium treatment. We have reviewed the available literature and provide a comprehensive summary detailing symptomatology of presentation, treatments utilized, electrocardiographic findings and patient prognoses. We have concluded that under the presumptive conditions that transient sinus node dysfunction will resolve with elimination of toxic concentrations of lithium, temporary chronotropic support provided by theophylline administration would be preferable to more invasive measures such as hemodialysis, temporary pacing, or implantation of a permanent pacemaker.

Background: Single chamber atrial pacemaker should be sufficient for patients with sinus node dysfunction (SND) with normal atrioventricular (AV) conduction. However, most patients undergo dual chamber pacemaker implantation because of concern of new onset AV block. The annual incidence of new AV block has been reported from 0.6 to 4.4 % in various studies. Objectives: Our aim is to assess mode survival in sinus node dysfunction with normal AV conduction patients implanted with AAIR. Methods: Patients who underwent single chamber atrial pacemaker implantation for SND with normal AV conduction between January 2014 and December 2021 were followed up for pacemaker device change, new onset AV block, bundle branch block, atrial fibrillation (AF), lead complications, reoperation and mortality rate. Results: A total of 113 patients underwent single chamber atrial pacemaker implantation for SND during the study period. Mean age was 55.6 ± 12.7 years. During a mean follow up of 48.7 ± 24.9 months, none of the patients required pacemaker device change to VVIR/DDDR. Nine patients underwent reoperation, 5 for lead dislodgment, 1 for high threshold, 1 for pocket site erosion and 3 for pulse generator change. None developed AV block or AF with slow ventricular rate. Only 4 patients developed AF (3 paroxysmal,1 permanent). There were 3 deaths during follow up and none were sudden deaths. Conclusion: Single chamber atrial pacing is an acceptable mode of pacing in patients with SND in developing countries. Development of AV conduction abnormalities is rare in this relatively younger population.

Clinically significant bradycardia is an uncommon problem in children, but one that can cause significant morbidity and sometimes necessitates implantation of a pacemaker. The most common causes of bradycardia are complete heart block (CHB), which can be congenital or acquired, and sinus node dysfunction, which is rare in children with structurally normal hearts. Pacemaker is indicated as therapy for the majority of children with CHB, and while early mortality is lower in postnatally diagnosed CHB than in fetal CHB, it is still up to 16%. In young children, less invasive transvenous pacemaker systems can be technically challenging to place and carry a high risk of complications, often necessitating surgical epicardial pacemaker placement, which usually entails a median sternotomy. We report three cases of pediatric patients referred for pacemaker implantation for different types of bradycardia, treated at our institution with oral albuterol with therapeutic results that avoided the need for surgical pacemaker implantation at that time. [ABSTRACT FROM AUTHOR]

Sinus node dysfunction (SND) with junctional rhythm (JR) is common after the Fontan operation. Atrial pacing (AP) restores atrioventricular (AV) synchrony, but the placement of a pacemaker carries significant morbidity. To study the impact of AP on echocardiographic parameters of function in Fontan patients with SND and JR. Nine Fontan patients with AP for SND and JR were prospectively studied with echocardiography in the following conditions—baseline paced rhythm, underlying JR and, if possible, slow-paced rhythm below their baseline paced rate (~ 10 bpm faster than their JR rate). Cardiac index was significantly lower in JR (3 ± 1.1 L/min/m2) vs AP (4.2 ± 1.4 L/min/m2; p = 0.002). Diastolic function also significantly worsened with increased ratio of early diastolic systemic AV valve inflow velocity to early diastolic systemic AV valve annulus velocity (E/e′ ratio) by tissue Doppler imaging (TDI) in JR (11.6 ± 4.6) vs AP (8.8 ± 2.2, p = 0.016). Pulmonary venous flow reversal was present in 7/9 patients in JR vs 0/9 in AP (p = 0.016). There were no significant differences in these echocardiographic measurements between the paced and slow-paced conditions. When compared to AP, JR was associated with a significant reduction in cardiac output and diastolic function, and an increased prevalence of pulmonary vein flow reversal. There were no differences between paced and slow-paced conditions, suggesting that AV synchrony rather than heart rate was primarily contributing to cardiac output. Further studies are needed to understand the chronic impact of JR on Fontan outcomes. [ABSTRACT FROM AUTHOR]

Cardiac pacemaker implantation after orthotopic heart transplantation declined dramatically after development of the bicaval anastomosis technique. However, much less is known about the rate, indications, and predictors of device implantation procedures with the current surgical technique. The purpose of this study was to evaluate the indications, patient characteristics, incidence, and survival related to cardiac implantable electronic device (CIED) implantation after heart transplantation. This was a single-center study of 399 consecutive adult recipients of orthotopic heart transplants with bicaval anastomosis from 1991 to 2017. The primary end point was freedom from pacemaker or implantable cardioverter-defibrillator (ICD) implantation, and the secondary end point was all-cause mortality. At the time of transplantation, the mean age of recipients was 50 ± 12 years and that of donors 31 ± 12 years. CIEDs were implanted in 8% of recipients (n = 31): 11 pacemakers (35%) for sinus node dysfunction, 17 (55%) for high-grade heart block, and 3 ICDs (10%) for the primary prevention of sudden cardiac death. Early CIED implantation (<30 days) was rare and absent for sinus node dysfunction. The risk for CIED implantation increased progressively during follow-up (0–30 years; median 11 years), with low-, moderate-, and high-risk periods between 0 and 10, between 10 and 20, and between 20 and 30 years, respectively. Recipients receiving CIEDs survived longer after transplantation (21 years vs 13 years; P <.01). Recipients receiving pacemakers for heart block were more likely to receive older donor hearts at the time of transplantation. The risk of pacemaker implantation increases progressively, while ICD implantation is rare. Donor age is the predominant risk factor for subsequent heart block. Early sinus node dysfunction requiring permanent pacing is rare. [ABSTRACT FROM AUTHOR]

Sinus node dysfunction with concomitant junctional rhythm (JR) is frequently observed among Fontan patients and has been recognized as a contributor to heart failure. The impact and management of JR is unclear. A survey was mailed to all members of the Pediatric and Congenital Electrophysiology society (PACES) and members were asked to forward the questionnaire to their non-electrophysiology colleagues. Responses were received from 154 physicians (88 electrophysiologists (EP's) and 66 non-EP's (46 pediatric cardiologists and 20 adult congenital cardiologists). There were few differences in the response between EP's and non-EP's. Overall, 57% recommended an annual ambulatory ECG (AECG). A significant majority (80%) opted to continue to follow patients with significant periods of JR on AECG as long as the patients were asymptomatic, and showed no echocardiographic signs of cardiac decompensation. However, 84% would place a pacemaker in a patient with JR who was having open chest surgery for other reasons. Finally, pacemaker placement would be performed by 91% if a patient with JR showed signs of heart failure. Most congenital cardiologists would not recommend pacemaker placement in asymptomatic Fontan patients with JR. Further studies are needed on the Fontan population to determine the impact of SND and JR on longer term outcomes and to determine the role and optimal timing of pacemaker placement in these patients. [ABSTRACT FROM AUTHOR]

Pacing indications in children are clearly defined, but whether an epicardial (EPI) or an endocardial (ENDO) pacemaker performs better remains to be elucidated. This systematic review and meta-analysis aimed to directly compare the incidence of pacemaker (PM) lead-related complications, mortality, hemothorax and venous occlusion between EPI and ENDO in children with atrioventricular block (AVB) or sinus node dysfunction (SND). Literature search was conducted in MEDLINE (via PubMed), Scopus by ELSEVIER, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and OpenGrey databases until June 25, 2022. Random-effects meta-analyses were performed to assess the pacing method's effect on lead failure, threshold rise, post-implantation infection and battery depletion and secondarily on all-cause mortality, hemothorax and venous occlusion. Several sensitivity analyses were also performed. Of 22 studies initially retrieved, 18 were deemed eligible for systematic review and 15 for meta-analysis. Of 1348 pediatric patients that underwent EPI or ENDO implantation, 542 (40.2%) had a diagnosis of congenital heart disease (CHD). EPI was significantly associated with higher possibility of PM-lead failure [pooled odds ratio (pOR) 3.00, 95% confidence interval (CI) 2.05–4.39; I2 = 0%]; while possibility for threshold rise, post-implantation infection and battery depletion did not differ between the PM types. Regarding the secondary outcome, the mortality rates between EPI and ENDO did not differ. In sensitivity analyses the results were consistent results between the two PM types. The findings suggest that EPI may be associated with increased PM-lead failure compared to ENDO while threshold rise, infection, battery depletion and mortality rates did not differ. [ABSTRACT FROM AUTHOR]

Background Screening for atrial fibrillation (AF) may reveal incidental arrhythmias of relevance. The aim of this study was to describe incidental arrhythmias detected during screening for AF in the STAR‐FIB (Predicting SilenT AtRial FIBrillation in Patients at High Thrombembolic Risk) cohort study. Methods and Results In the STAR‐FIB cohort study, we screened hospitalized patients for AF with 3 repeat 7‐day Holter ECGs. We analyzed all Holter ECGs for the presence of the following incidental arrhythmias: (1) sinus node dysfunction, defined as sinus pause of ≥3 seconds’ duration; (2) second‐degree (including Wenckebach) or higher‐degree atrioventricular block (AVB); (3) sustained supraventricular tachycardia of ≥30 seconds’ duration; and (4) sustained ventricular tachycardia of ≥30 seconds’ duration. We furthermore report treatment decisions because of incidental arrhythmias. A total of 2077 Holter ECGs were performed in 794 patients (mean age, 74.7 years; 49% women), resulting in a mean cumulative duration of analyzable ECG signal of 414±136 hours/patient. We found incidental arrhythmias in 94 patients (11.8%). Among these were sinus node dysfunction in 14 patients (1.8%), AVB in 41 (5.2%), supraventricular tachycardia in 42 (5.3%), and ventricular tachycardia in 2 (0.3%). Second‐degree AVB was found in 23 patients (2.9%), 2:1 AVB in 10 (1.3%), and complete AVB in 8 (1%). Subsequently, 8 patients underwent pacemaker implantation, 1 for sinus node dysfunction (post‐AF conversion pause of 9 seconds) and 7 for advanced AVB. One patient had an implantable cardioverter‐defibrillator implanted for syncopal ventricular tachycardia. Conclusions Incidental arrhythmias were frequently detected during screening for AF in the STAR‐FIB study and resulted in device therapy in 1.1% of our cohort patients.

Hypervagotonic sinus node dysfunction (SND) is a form of SND with sinus bradycardia caused by enhanced vagal tone. Indirect proof of hypervagotonia as the mechanism can be inferred from resolution of bradycardia following atropine infusion. In symptomatic patients, pacemaker implantation is recommended. We describe cardioneuroablation as a treatment for hypervagotonic SND.

BackgroundPathogenic/Likely pathogenic variants in DSP-encoded desmoplakin are strongly associated with arrhythmogenic cardiomyopathy (ACM). However, their contribution towards sinus node dysfunction has not been well-delineated.Case summaryA 74-year-old man with a pathogenic variant of DSP-encoded desmoplakin (c.478C >T; p.Arg160X) but no evidence of ACM presented with one episode of syncope in the setting of a gastrointestinal illness. Workup including echocardiography, cardiac magnetic resonance imaging, and Holter monitor did not show evidence of ACM or significant arrhythmias. One month later, he experienced several closely-spaced episodes of syncope associated with long sinus pauses and sinus arrest documented on telemetry. He underwent urgent dual chamber pacemaker implantation, during which a ventricular programmed stimulation study was performed and was negative for sustained ventricular arrhythmias. His syncopal episodes resolved and he had no recurrent events on three-month follow-up.DiscussionAs highlighted here, DSP-encoded desmoplakin pathogenic/Likely pathogenic variants may contribute to isolated sinus node dysfunction. This clinical link should be further explored in larger studies involving patients with DSP variants.

An 82-year-old woman presented with cough, chest pain, and presyncope. She was found to have 1:1 typical atrial flutter with cycle length of 290 ms. After administration of IV diltiazem, she developed symptomatic bradycardia. She was admitted for permanent pacemaker (PPM) placement due to tachy/brady syndrome. Pre-PPM echocardiogram demonstrated a 1.3 × 0.8 cm infiltrating right atrial mass, causing a "slit-like" superior vena cava, likely responsible for her slow flutter cycle length and sinus node dysfunction. Due to anatomic compression of the SVC, PPM placement from superior approach was not possible; leadless PPM was placed via femoral approach. Pathology ultimately diagnosed high-grade B cell lymphoma with MYC and BCL2 rearrangements. [ABSTRACT FROM AUTHOR]

Mutations in the KCNJ5 gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K+ (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K+ current (IK,ACh). hiPSC-CMs with the W101C KCNJ5 mutation (hiPSCW101C-CM) had a constitutively active IK,ACh under baseline conditions; the application of carbachol was able to increase IK,ACh, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSCW101C-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction. [ABSTRACT FROM AUTHOR]

In rare cases, an HSV-Encephalitis can lead to sinus node dysfunction, as was the case in this 70-year old woman who suffered from recurrent syncopes. Diagnostic work-up showed sinus bradycardias and short-lasting sinus arrests, primarily considered to be of cardiac etiology. After development of fever and neurological alteration, an HSV1 encephalitis was diagnosed. As our research of the current literature showed, the connection between the two is not completely clear. The HSVtypical infestation of the insular cortex, which influences the autonomic nervous system, should be discussed by all means. However, due to cessation of arrhythmia after seizure-suppressing therapy, we suspected an epileptic cause in this case. This shows the importance of a thorough differential diagnostic evaluation. [ABSTRACT FROM AUTHOR]

Background: A pacemaker implantation is not indicated in cases of reversible high‐degree symptomatic sinus node dysfunction (SND) and atrioventricular block (AVB). However, it remains uncertain whether these reversible automaticity/conduction disorders may recur in some patients at follow‐up, in the absence of reversible cause. This retrospective study aimed to determine the incidence and predictive factors of permanent pacemaker (PPM) implantation at follow‐up and after reversible high‐degree SND/AVB. Methods: Based on medical electronic files codes, we identified patients who were hospitalized in our cardiac intensive care unit between January 2003 and December 2020 due to reversible high‐degree SND/AVB and who were discharged from the hospital alive and without PPM implantation. Acute myocardial infarction and post‐cardiac surgery patients were excluded. We categorized the patients according to the need for PPM at follow‐up due to non‐reversible high‐degree SND/AVB. Results: Of the 93 patients included, 26 patients (28%) were readmitted for PPM implantation at follow‐up after hospital discharge. Among baseline characteristics, compared with patients who did not have high‐degree SND/AVB recurrence, those who had subsequent PPM implantation had less frequent previous hypertension (70% vs. 46%, p =.031). Regarding the initial causes of reversible SND/AVB, isolated hyperkalemia was found more often in the patients readmitted for PPM (19% vs. 3% vs. p =.017). Moreover, recurrence of high‐degree SND/AVB was significantly associated with the presence of intraventricular conduction disorders (either bundle branch block or left bundle branch hemiblock) on ECG at discharge (36% in patients without PPM vs. 68% in PPM patients, p =.012). Conclusion: Almost one third of the patients discharged alive from the hospital after a reversible high‐degree SND/AVB needed a pacemaker implantation at follow‐up. Complete bundle branch block or left bundle branch hemiblock on discharge ECG after recovery of atrioventricular conduction and/or sinus automaticity was associated with a greater risk of recurrence leading to pacemaker implantation. [ABSTRACT FROM AUTHOR]

Background: Ongoing research on Coronavirus Disease 2019 (COVID-19) infection has revealed that it is associated with serious damage to many organs, not only the lungs. This infection can also affect the cardiovascular system and lead to serious cardiac pathologies. In this article, we present a case of transient bradyarrhythmia in a patient who was diagnosed with COVID-19 and recovered spontaneously with treatment. Case Report: A 74-year-old male patient was hospitalized with symptomatic COVID-19 infection. At the time of hospitalization, the patient was asymptomatic from a cardiac standpoint, but was found to have sinoatrial exit block type 2-2, intermittent Mobitz type 2 atrioventricular block, and sinus bradycardia. The medical team decided to closely monitor the patient, who responded well to COVID-19 treatment and did not develop bradyarrhythmia as his symptoms improved. Conclusion: Patients with COVID-19 infection should be closely monitored for bradyarrhythmia. Permanent pacemaker should not be rushed in these patients. [ABSTRACT FROM AUTHOR]

Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of GIRK4 (Kir3.4) in cardiac physiology and pathophysiology has yet to be completely understood. Within the heart, the KACh channel, consisting of two GIRK1 and two GIRK4 subunits, plays a major role in modulating the parasympathetic nervous system's influence on cardiac physiology. Being that GIRK4 is necessary for the functional KACh channel, KCNJ5, which encodes GIRK4, it presents as a therapeutic target for cardiovascular pathology. Human variants in KCNJ5 have been identified in familial hyperaldosteronism type III, long QT syndrome, atrial fibrillation, and sinus node dysfunction. Here, we explore the relevance of KCNJ5 in each of these diseases. Further, we address the limitations and complexities of discerning the role of KCNJ5 in cardiovascular pathophysiology, as identical human variants of KCNJ5 have been identified in several diseases with overlapping pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Bradyarrhythmias including sinus node dysfunction (SND) and atrioventricular block (AVB) can necessitate pacemaker (PPM) implantation in orthotopic heart transplant (OHT) recipients. Prior studies have shown conflicting findings regarding the effect of PPM implantation on survival. We evaluated the effect of PPM indication on long‐term re‐transplant‐free survival in OHT patients. Methods: We conducted a retrospective cohort study of OHT patients at UCLA Medical Center from 1985 to 2018. Indication for PPM (SND, AVB) was identified. Cox proportional hazards model with pacemaker implantation as a time‐varying covariate was used to evaluate its effect on the primary endpoint of retransplant or death. We included 1609 OHTs in 1511 adult patients with median follow‐up of 12 years. Results: At transplant, patients were aged 53 ± 13 years and 1125 (74.5%) were male. Pacemakers were implanted in 109 (7.2%) patients; 65 for SND (4.3%) and 43 for AVB (2.8%). Repeat OHT was performed in 103 (6.4%) cases and 798 (52.8%) patients died during the follow‐up period. The risk of the primary endpoint was significantly higher in patients requiring PPM for AVB (HR 3.0, 95% CI 2.1–4.2, p <.01) after controlling for age at OHT, gender, hypertension, diabetes, renal disease, history of repeat OHT, acute rejection, transplant coronary vasculopathy, and atrial fibrillation, but not PPM for SND (HR 1.0, 95% CI 0.70–1.4, p = 1.0). Conclusions: Patients who required PPM for AVB, but not SND, were at significantly higher risk of death or retransplant compared to patients who did not require PPM. [ABSTRACT FROM AUTHOR]

Objectives: To investigate primary and secondary surgical outcomes following transcaval repair (TCR), modified Warden repair, and transatrial repair techniques for partial anomalous pulmonary venous connections (PAPVCs) and sinus venosus atrial septal defects (ASDs). Methods: This is an observational cohort clinical study. Patients who underwent TCR, modified Warden repair, and transatrial surgical repair for PAPVC and ASD between January 2003 and October 2019 at our institution were included in the study. Patients had one of the surgical procedures based on the anatomy of the defect. Results: Ten patients, seven (70%) males and three (30%) females, were included in the analysis. Seven patients underwent TCR, two patients the modified Warden technique, and one patient underwent transatrial surgical repair. Mean age was 57 years ± 14.7. Mean EuroScore II was 3.4 ± 3.5. The baseline left ventricle ejection fraction was 45 ± 6.5%. No patient had previous stroke, pacemaker (PM) implantation, or myocardial infarction. Total cardiopulmonary bypass and cross-clamping time were 123 ± 72.5 and 100 ± 48.5 min, respectively. Mean mechanical ventilation, mean intensive care unit, and mean hospital length of stay for the transcaval, modified Warden, and transatrial groups were 4.6 ± 10.7, 5.7 ± 8.8, and 10.5 ± 9.2 days, respectively. Superior caval or pulmonary venous obstruction, sinus node dysfunction, and PM implantation were not present at follow-up. The patient who underwent transatrial repair had died at 5.5-year follow-up due to myocardial infarction. Total survival rate at 6 years was 90%. Conclusions: The findings from this study elicit that all three techniques have low postoperative morbidity and are feasible and reliable procedures.

Aims: IMPROVE Brady assessed whether a process improvement intervention could increase adoption of guideline-based therapy in sinus node dysfunction (SND) patients. Methods: /Results: IMPROVE Brady was a sequential, prospective, quality improvement initiative conducted in India and Bangladesh. Patients with symptomatic bradycardia were enrolled. In Phase I, physicians assessed and treated patients per standard care. Phase II began after implementing educational materials for physicians and patients. Primary objectives were to evaluate the impact of the intervention on SND diagnosis and pacemaker (PPM) implant. SF-12 quality of life (QoL) and Zarit burden surveys were collected pre- and post-PPM implant.A total of 978 patients were enrolled (57.7 ± 14.8 years, 75% male), 508 in Phase I and 470 in Phase II. The diagnosis of SND and implantation of PPM increased significantly from Phase I to Phase II (72% vs. 87%, P

Bradyarrhythmias are adequately treated with pacemakers. There are different pacing modes (single-chamber, dual-chamber, cardiac resynchronisation therapy [CRT] and conduction system pacing [CSP]) and a choice between leadless or transvenous pacemakers. The expected pacing need is important for determining optimal pacing mode and device type. This study aimed to evaluate atrial pacing (AP) and ventricular pacing (VP) percentages over time for the most common pacing indications. Included patients were aged ≥18 years with a dual-chamber rate-modulated [DDD(R)] pacemaker implantation and ≥1 year of follow-up at a tertiary centre between January 2008 and January 2020. Baseline characteristics, AP and VP at yearly follow-up visits up to 6 years after implantation were retrieved from the medical records. A total of 381 patients were included. Primary pacing indications were incomplete atrioventricular block (AVB) in 85 (22%), complete AVB in 156 (41%) and sinus node dysfunction (SND) in 140 (37%) patients. Mean age at implantation was 71±14, 69±17 and 68±14 years, respectively (p=0.23). Median follow-up was 42 months (25–68 months). Overall, AP was highest in SND with median 37% (7%–75%) versus 7% (1%–26%) in incomplete AVB and 3% (1%–16%) in complete AVB (p<0.001); VP was highest in complete AVB with median 98% (43%–100%) versus 44% (7%–94%) in incomplete AVB and 3% (1%–14%) in SND (p<0.001). Ventricular pacing significantly increased over time in patients with incomplete AVB and SND (both p=0.001). These results confirm the pathophysiology of different pacing indications, causing clear differences in pacing need and expected battery longevity. They may help guide optimal pacing mode and suitability for leadless or physiological pacing. [ABSTRACT FROM AUTHOR]

Aims In bradycardia patients treated with dual-chamber pacing, we aimed to evaluate whether pacing with atrioventricular (AV) delay management [AV hysteresis (AVH)], compared with standard pacing with fixed AV delays, reduces unnecessary ventricular pacing percentage (VPP) and is associated with better clinical outcomes. Main study endpoints were the incidence of heart failure hospitalizations (HFH), persistent atrial fibrillation (AF), and cardiac death. Methods and results Data from two identical prospective observational studies, BRADYCARE I in the USA and BRADYCARE II in Europe, Africa, and Asia, were pooled. Overall, 2592 patients (75 ± 10 years, 45.1% female, 50% with AVH) had complete clinical and device data at 1-year follow-up and were analysed. Primary pacing indication was sinus node disease (SND) in 1177 (45.4%), AV block (AVB) in 974 (37.6%), and other indications in 441 (17.0%) patients. Pacing with AVH, compared with standard pacing, was associated with a lower 1-year incidence of HFH [1.3% vs. 3.1%, relative risk reduction (RRR) 57.5%, P = 0.002] and of persistent AF (5.3% vs. 7.7%, RRR = 31.1%, P = 0.028). Cardiac mortality was not different between groups (1.0% vs. 1.4%, RRR = 27.8%, P = 0.366). Pacing with AVH, compared with standard pacing, was associated with a lower (P < 0.001) median VPP in all patients (7% vs. 75%), in SND (3% vs. 44%), in AVB (25% vs. 98%), and in patients with other pacing indications (3% vs. 47%). Conclusion Cardiac pacing with AV delay management via AVH is associated with reduced 1-year incidence of HFH and persistent AF, most likely due to a reduction in VPP compared to standard pacing. [ABSTRACT FROM AUTHOR]

Syncope is a frequently encountered condition in the emergency room, with vagal syncope being the most prevalent form. However, overlapping symptoms can pose diagnostic challenges when distinguishing between vagal syncope and symptomatic sinus node dysfunction. A comprehensive history and careful evaluation of hemodynamics and electrocardiogram findings are crucial for accurate differentiation. Vagal syncope is typically associated with an upright posture, and supine syncope is considered atypical. In this case report, we describe an intriguing instance of supine vagal syncope, highlighting the importance of correct diagnosis to avoid unnecessary pacemaker implantation. [ABSTRACT FROM AUTHOR]

The sinoatrial node (SAN) is the primary pacemaker of the heart. Normal SAN function is crucial in maintaining proper cardiac rhythm and contraction. Sinus node dysfunction (SND) is due to abnormalities within the SAN, which can affect the heartbeat frequency, regularity, and the propagation of electrical pulses through the cardiac conduction system. As a result, SND often increases the risk of cardiac arrhythmias. SND is most commonly seen as a disease of the elderly given the role of degenerative fibrosis as well as other age-dependent changes in its pathogenesis. Despite the prevalence of SND, current treatment is limited to pacemaker implantation, which is associated with substantial medical costs and complications. Emerging evidence has identified various genetic abnormalities that can cause SND, shedding light on the molecular underpinnings of SND. Identification of these molecular mechanisms and pathways implicated in the pathogenesis of SND is hoped to identify novel therapeutic targets for the development of more effective therapies for this disease. In this review article, we examine the anatomy of the SAN and the pathophysiology and epidemiology of SND. We then discuss in detail the most common genetic mutations correlated with SND and provide our perspectives on future research and therapeutic opportunities in this field. [ABSTRACT FROM AUTHOR]

Atrial flutter (AFL) is the second most common atrial tachyarrhythmia after atrial fibrillation. Catheter ablation (CA) for typical AFL is well‐established and has a high success rate and adequate safety. However, sick sinus syndrome (SSS) occasionally occurs when long‐term, persistent AFL is terminated by ablation. Sinus node function cannot be assessed during AFL, and the preoperative prediction of underlying SSS has not yet been investigated. When this situation occurs, pacemaker implantation is often necessary. Here, we report a case of SSS after persistent AFL CA. [ABSTRACT FROM AUTHOR]

Sinus node dysfunction is a common arrhythmia disorder with a high incidence and significant social and economic burden. Currently, there are no effective drugs for treating chronic sinus node dysfunction. The disease is associated with ion channel disturbances caused by aging, fibrosis, inflammation, oxidative stress, and autonomic dysfunction. Natural active substances and Chinese herbal medicines have been widely used and extensively studied in the medical community for the treatment of arrhythmias. Multiple studies have demonstrated that various active ingredients and Chinese herbal medicines, such as astragaloside IV, quercetin, and ginsenosides, exhibit antioxidant effects, reduce fibrosis, and maintain ion channel stability, providing promising drugs for treating sinus node dysfunction. This article summarizes the research progress on natural active ingredients and Chinese herbal formulas that regulate sick sinoatrial node function, providing valuable references for the treatment of sinus node dysfunction.

BackgroundThere is no concise evidence or clinical guidelines regarding the incidence of sinus node dysfunction (SND) and permanent pacemaker (PPM) implantation following cardiac surgeries and their management approaches.ObjectiveWe aim to systematically review current evidence on the prevalence of SND, PPM implantation concerning it, and its risk factors in patients undergoing cardiac surgery.MethodFour electronic databases (Cochrane Library, Medline, SCOPUS, and Web of Science) were systematically searched for articles regarding SND after cardiovascular surgeries and reviewed by two independent researchers, and a third review in case of discrepancies. Using the random-effects model, a proportion meta-analysis was performed on data regarding PPM implantation. Subgroup analysis was performed for different interventions, and the possible effect of different covariates was evaluated using meta-regression.ResultsFrom the initial 2012 unique records, 87 were included in the study, and results were extracted. Pooled data from 38,519 patients indicated that the overall prevalence of PPM implantation due to SND after cardiac surgery was 2.87% (95% CI [2.09; 3.76]). The incidence of PPM implantation in the first post-surgical month was 2.707% (95% CI [1.657; 3.952]). Among the four main intervention groups, including valve, maze, valve-maze, and combined surgeries, maze surgery was associated with the highest prevalence (4.93%; CI [3.24; 6.92]). The pooled prevalence of SND among studies was 13.71% (95% CI [8.13; 20.33]). No significant relationship was observed between PPM implantation and age, gender, cardiopulmonary bypass time, or aortic cross-clamp time.ConclusionBased on the present report, patients undergoing the maze and maze-valve procedures are at higher risk of post-op SND, whereas lone valve surgery had the lowest prevalence of PPM implantation.Systematic Review RegistrationPROSPERO (CRD42022341896).

Abstract Atrial flutter (AFL) is the second most common atrial tachyarrhythmia after atrial fibrillation. Catheter ablation (CA) for typical AFL is well‐established and has a high success rate and adequate safety. However, sick sinus syndrome (SSS) occasionally occurs when long‐term, persistent AFL is terminated by ablation. Sinus node function cannot be assessed during AFL, and the preoperative prediction of underlying SSS has not yet been investigated. When this situation occurs, pacemaker implantation is often necessary. Here, we report a case of SSS after persistent AFL CA.

Sinus node dysfunction is a multifaceted disorder with variable manifestations, the prevalence of which increases with age. In a specific group of patients, excessive vagal activity may be the sole cause for this condition. These patients are characterized as having recurrent daytime symptoms attributed to bradyarrhythmia, no evidence of organic sinus node lesions, cardiac vagal overactivation, and are non-elderly. For sinus node dysfunction patients, a permanent pacemaker implantation appears to be the ultimate solution, although it is not an etiological treatment. Cardioneuroablation is a promising emerging therapy that can fundamentally eliminate symptoms in a highly selective sub-set of sinus node dysfunction patients by cardiac vagal nerve denervation. Denervation with ablation for vagal-induced sinus node dysfunction can effectively improve sinus bradycardia and reduce syncope. To date, guidelines for selection of suitable candidates for cardioneuroablation remain lacking. The primary objective of this study was to distinguish the nature of abnormal sinus node function and to find methods for quantifying vagal tone. Clear selection criteria could help physicians in identification of patients with autonomic imbalance, thereby maximizing patient benefits and the success rate of cardioneuroablations. [ABSTRACT FROM AUTHOR]

A 46‐year‐old woman was admitted with coronavirus disease‐2019 infection. Symptomatic sinus bradycardia occurred, followed by congestive heart failure. Therapeutics such as isoproterenol, theophylline, and cilostazol could not safely improve her symptoms. She underwent pacemaker implantation 53 days after admission. Atrial pacing remained was at 60% after 6 months. To recognize that sinus bradycardia initiated by COVID‐19 can cause congestive heart failure and identify COVID‐19 as a potential etiology of sinus node dysfunction. Although it is usually reversible, it may persist in some patients. [ABSTRACT FROM AUTHOR]

Background: Even a short duration of paroxysmal episodes of atrial fibrillation (AF) is associated with sinus node (SN) remodeling and a reduced SN reserve or dysfunction. The number of earliest atrial activation sites (EASs) during sinus rhythm decreases according to the decrease in the SN reserve. Objective: We sought to evaluate the EASs during sinus rhythm using an ultrahigh‐density mapping system. Methods: This study included 35 patients (supraventricular tachycardia [SVT]/paroxysmal atrial fibrillation [PAF]/persistent atrial fibrillation [PsAF] = 5/21/9) who underwent ultrahigh‐resolution endocardial mapping of the SN area at rest and during β‐stimulation. The number of EASs was determined by the Lumipoint™ algorithm. Results: The number of EASs was greatest in SVT patients both at rest (SVT/PAF/PsAF = 1.4 ± 0.8/1.0 ± 0/1.0 ± 0, p =.04) and during β‐stimulation (SVT/PAF/PsAF = 2.6 ± 1.0/1.3 ± 0.6/1.0 ± 0, p <.01). The number significantly increased with β‐stimulation as compared to baseline in the PAF patients (p =.02), but not in the PsAF patients. The brain natriuretic peptide (BNP) level was significantly higher in AF than SVT patients (SVT/PAF/PsAF = 12.3 [10.1–14.5]/25.7 [14.8–36.0]/73.4 [57.6–140] pg/ml, p <.01). In the PAF patients, the BNP level was significantly higher in those with unicentric EASs than multicentric EASs during β‐stimulation (28.1 [19.1–46.5] vs. 13.1 [9.4–26.9] pg/ml, p =.03), and the optimal cutoff point for the BNP level predicting unicentric EASs was 21.8 pg/ml (sensitivity 82.6%; specificity 85.7%). Conclusions: AF patients have a smaller number of EASs and poorer response to β‐stimulation than non‐AF patients. An elevated BNP level might predict subclinical SN dysfunction in patients with PAF. [ABSTRACT FROM AUTHOR]

Objectives: To investigate primary and secondary surgical outcomes following transcaval repair (TCR), modifiedWarden repair, and transatrial repair techniques for partial anomalous pulmonary venous connections (PAPVCs) and sinus venosus atrial septal defects (ASDs). Methods: This is an observational cohort clinical study. Patients who underwent TCR, modified Warden repair, and transatrial surgical repair for PAPVC and ASD between January 2003 and October 2019 at our institution were included in the study. Patients had one of the surgical procedures based on the anatomy of the defect. Results: Ten patients, seven (70%) males and three (30%) females, were included in the analysis. Seven patients underwent TCR, two patients the modified Warden technique, and one patient underwent transatrial surgical repair. Mean age was 57 years ± 14.7. Mean EuroScore II was 3.4 ± 3.5. The baseline left ventricle ejection fraction was 45 ± 6.5%. No patient had previous stroke, pacemaker (PM) implantation, or myocardial infarction. Total cardiopulmonary bypass and cross-clamping time were 123 ± 72.5 and 100 ± 48.5 min, respectively. Mean mechanical ventilation, mean intensive care unit, and mean hospital length of stay for the transcaval, modified Warden, and transatrial groups were 4.6 ± 10.7, 5.7 ± 8.8, and 10.5 ± 9.2 days, respectively. Superior caval or pulmonary venous obstruction, sinus node dysfunction, and PM implantation were not present at follow-up. The patient who underwent transatrial repair had died at 5.5-year follow-up due to myocardial infarction. Total survival rate at 6 years was 90%. Conclusions: The findings from this study elicit that all three techniques have low postoperative morbidity and are feasible and reliable procedures. [ABSTRACT FROM AUTHOR]

Mutations in the KCNJ5 gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K+ (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K+ current (IK,ACh). hiPSC-CMs with the W101C KCNJ5 mutation (hiPSCW101C-CM) had a constitutively active IK,ACh under baseline conditions; the application of carbachol was able to increase IK,ACh, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSCW101C-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction.