Temporary Sinus Node Dysfunction following Ablation of Atrial Fibrillation in Patients with Aberrancy of the Sinus Node Artery: A case series.

OBJECTIVES: To investigate sinus node dysfunction (SND) as a rare complication following surgical and catheter atrial fibrillation (AF) ablation in patients with an aberrant sinus node artery (SNA). METHODS: Retrospective analysis of 3 patients with an aberrant SNA that underwent different AF ablation procedures: 1 concomitant to aortic valve replacement, 1 thoracoscopic hybrid AF ablation, and 1 catheter AF ablation. RESULTS: All patients experienced temporary SND perioperatively. In the first patient sinus rhythm (SR) recovered by the sixth postoperative day. In the second patient SR returned by the 14th postoperative day. The third patient had a sinus arrest during ablation but restored to SR immediately post-procedure. All patients had normal SR at three-months follow-up. CONCLUSIONS: Awareness of SNA anatomy can help to prevent iatrogenic SND during AF ablation. If SND occurs, a wait-and-see approach is recommended, as sinus node function seems to recover. Since SND recovers, the benefits of posterior wall isolation could outweigh the disadvantages of temporary SND.

A Rare Case of Complete Heart Block and Takotsubo Cardiomyopathy in an Elderly Patient: A Case Report.

Although Takotsubo cardiomyopathy (TC) is often linked to various tachyarrhythmias, the coexistence of Takotsubo cardiomyopathy and complete heart block is rare, and the cause-and-effect relationship remains unclear. We present the case of an 83-year-old female with a history of known second-degree atrioventricular (AV) block who presented with syncopal episodes and bradycardia. She was diagnosed with a complete heart block requiring a dual-chamber pacemaker. Upon case review, transthoracic echocardiography revealed severe apical hypokinesis, prompting coronary angiography, which showed normal coronary arteries, consistent with Takotsubo cardiomyopathy. This case explores the relationship between Takotsubo cardiomyopathy and complete heart block, as well as the potential pathophysiological mechanisms involved.

GLP-1 increases heart rate by a direct action on the sinus node.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. METHODS AND RESULTS: We employed a large animal model, the female landrace pig, and used multiple in-vivo and ex-vivo approaches including pharmacological challenges, electrophysiology and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta or combined alpha-beta blockade), ganglionic blockade (hexamethonium) nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing (snRNAseq) showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. CONCLUSION: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.

High initial heart rate score is an independent predictor of new atrial high-rate episodes in pacemaker patients with sinus node dysfunction.

BACKGROUND: Heart rate score (HRSc), the percentage of atrial depolarizations in the largest paced and sensed 10-beats/min histogram bin recorded in cardiac devices, is associated with several adverse outcomes, but it remains uncertain whether HRSc independently predicts atrial high-rate episodes (AHREs) in patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation. OBJECTIVE: This study aimed to determine whether initial HRSc after PM implantation predicts new-onset AHREs in patients with SND. METHODS: Patients had Boston Scientific PMs implanted for SND from 2012 to 2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial fibrillation before PM implantation or AHREs within 3 months after implantation. Subsequent AHREs after implantation were evaluated and correlated with HRSc. RESULTS: During 48.9 (interquartile range, 25.7-50.4) months, 130 consecutive PM patients (76 ± 10 years; 40% male) had a median initial HRSc of 74% (57%-86%). AHREs defined by >1%, >6 h/d burden, and atrial tachycardia response events >24 hours developed in 27 of 130 (21%), 15 of 130 (12%), and 9 of 130 (7%), respectively. For each definition, patients with HRSc ≥80% had higher occurrence of AHREs than those with HRSc <80% (both P = .008, log-rank test). After adjustment for age, race, comorbidities, left ventricular ejection fraction, left atrial diameter, and cumulative percentage of right atrial and right ventricular pacing, initial HRSc ≥80% (hazard ratio, 3.33; 95% CI, 1.35-8.18; P = .009) and male sex (hazard ratio, 2.59; 95% CI, 1.06-6.33; P = .04) independently predicted AHREs. CONCLUSION: HRSc ≥80% is associated with new-onset, device-determined AHREs for patients undergoing PM implantation for SND. HRSc may have prognostic and therapeutic implications.

The electrophysiological effects of Tongyang Huoxue granules on the ignition phase during hypoxia/reoxygenation injury in sinoatrial node cells.

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 (I NCX) and L-type calcium channel (I CaL) 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 I NCX increased in response to TYHX (200 and 400 µg/mL), while TYHX enhanced I CaL current density in H/R SANCs, with 400 µg/mL exhibiting greater efficacy. Additionally, TYHX regulated the gating mechanisms of I CaL 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 τ1 with 400 µg/mL, and extended the slow inactivation time constant τ2 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.

Procedural and cardiovascular outcomes of geriatric vs non-geriatric patients undergoing permanent pacemaker implantation - a nationwide cohort analysis.

BACKGROUND: Permanent pacemaker implantation is increasing exponentially to treat atrio-ventricular block and symptomatic bradyarrhythmia. Despite being a minor surgery, immediate complications such as pocket infection, pocket hematoma, pneumothorax, hemopericardium, and lead displacement do occur. METHODS: The Nationwide Inpatient Sample was queried from 2016 to 2018 to identify patients with pacemakers using ICD-10 procedure code. The Chi-square test was used for statistical analysis. RESULTS: The sample size consisted of 443,460 patients with a pacemaker, 26% were <70 years (male 57%, mean age of (60.6±9.7) yr, Caucasian 70%) and 74% were ≥70 years (male 50%, mean age of (81.4±5.9) yr, Caucasian 79%). Upon comparison of rates in the young vs elderly: mortality (1.6% vs 1.5%; P<0.01), obesity (26% vs 13%; P<0.001), coronary artery disease (40% vs 49%; P<0.001), HTN (74% vs 87%; P<0.01), anemia (4% vs 5%; P<0.01), atrial fibrillation (34% vs 49%; P<0.01), peripheral artery disease (1.7% vs 3%; P<0.01), CHF (31% vs 39%; P<0.001), diabetes (31% vs 27.4%; P<0.01), vascular complications (1.1% vs 1.2%; P<0.01), pocket hematoma (0.5% vs 0.8%; P<0.01), AKI (16% vs 21%; P<0.01), hemopericardium (0.1% vs 0.1%; P = 0.1), hemothorax (0.3% vs 0.2%; P<0.01), cardiac tamponade (0.4% vs 0.5%; P<0.01), pericardiocentesis (0.4% vs 0.4%; P<0.01), cardiogenic shock (4% vs 2.3%; P<0.01), respiratory complications (1.9% vs 0.9%; P<0.01), mechanical ventilation (5.1% vs 2.9%; P<0.01); post-op bleed (0.5% vs 0.3%; P<0.01), need for transfusion (4.8% vs 3.8%; P<0.01), severe sepsis (0.6% vs 0.5%; P<0.01 ), septic shock (2% vs 1%; P<0.01), bacteraemia (0.8% vs 0.4%; P<0.01), lead dislodgement (1.4% vs 1.1%; P<0.01). CONCLUSIONS: Our study revealed that the overall complication rates were lower in the elderly despite higher co-morbidities. This aligns with previous studies which showed lower rates in the elderly. Hence providers should not hesitate to provide guideline driven pacemaker placement in the elderly especially in patients with good life expectancy.

Married to the Pacemaker: An Autobiographical Case Report of Sick Sinus Syndrome.

I, the author of this case report, was on beta blockers, initially atenolol and later on nebivolol, for my "systemic hypertension" illness. After attending the National Pulmonary Conference, I fell during the return journey on the express highway, became unconscious, and reached the tertiary care hospital of the medical college at the end of the day. The electrocardiogram was suggestive of a "complete heart block.". They immediately implanted a temporary pacemaker and transferred me to the cardiac care unit. I was discharged after five days of stay in the hospital, as the Holter study concluded to be normal. After about two weeks, I felt lightheadedness and giddiness for a fraction of a second. An eminent senior cardiologist in my hometown advised Holter's study; this time, it was suggestive of long pauses. A permanent pacemaker was implanted with the diagnosis of sick sinus syndrome. This autobiographical case report hopes to shed light on more advanced cardiac screening in the search for the etiology of clinical symptoms.

Intracardiac echocardiography guided anatomical ablation of the arcuate ridge for drug refractory inappropriate sinus tachycardia.

INTRODUCTION: Inappropriate sinus tachycardia (IST) is a common condition with frequently not tolerated beta-blockers or ivabradine and a high rate of complication in ablation strategy; we describe an alternative anatomical approach of sinus node (SN) modulation. METHODS: This retrospective study describes a case series of 6 patients from two centers diagnosed with symptomatic IST undergoing SN ablation. RESULTS: The mean age was 40.6 ± 13.9 years; five of the six patients were female, 100% of patients reported heart palpitations, and 66% reported dizziness, the average heart rate (HR) on a 24-h Holter was 93.2 ± 7.9 bpm. HR during the first stage of a stress test using a standard Bruce protocol was 150 ± 70 bpm, The average HR on 24-h Holter postablation was 75 ± 5.6 bpm, the sinus rate HR during stage 1 of a Bruce protocol exercise stress test was 120 ± 10 bpm. CONCLUSION: This is the first case series reporting the acute and long-term results of a novel anatomical approach for SN modulation to treat IST targeting the arcuate ridge (AR) under intracardiac echography (ICE) guidance. The novel anatomic ICE-guided catheter ablation approach aimed to identify the earliest activation at the AR with an extension of RF lesions toward its septal region seems effective and safe to modulate the SN in symptomatic patients with IST refractory to medical treatment.

Severe Sinus Dysfunction in the Context of Chronic Lithium Intoxication and Poorly Controlled Hypothyroidism.

Cardiotoxicity associated with lithium is not a common event; however, it is potentially life-threatening, manifesting electrocardiographically with sinoatrial blocks, high-degree atrioventricular blocks, QT prolongation, and ventricular tachyarrhythmias. This case report presents a patient with severe sinus dysfunction in a clinically severe presentation secondary to cardiogenic shock. The patient sought medical attention for a one-week history of non-anginal chest pain, dizziness without syncope, generalized weakness, and somnolence progressing to bedridden status in the days preceding hospital admission. Laboratory findings revealed elevated blood levels of lithium and thyroid-stimulating hormone (TSH), along with concomitant Acute Kidney Injury Network (AKIN) II acute kidney injury. Subsequently, the patient was admitted to the intensive care unit, where persistent extreme sinus bradycardia of 30 bpm (beats per minute) with sinus pauses without ischemic changes was observed. The patient received supportive treatment, including renal replacement therapy, resulting in complete recovery of hemodynamic status without the need for long-term cardiac conduction devices.

Refractory Inappropriate Sinus Tachycardia Treated with Pulsed-field Ablation of the Sinus Node: A Breath of Fresh Air.

The pathogenesis of inappropriate sinus tachycardia is not well understood, and the symptoms of inappropriate sinus tachycardia can be difficult to manage. Here, we present a case of inappropriate sinus tachycardia refractory to medical therapy and discuss our approach to sinus node modification by catheter ablation.

Three-year incidence of pacemaker implantation in patients with atrial fibrillation and sinus node dysfunction receiving ablation versus antiarrhythmic drugs.

BACKGROUND: Sinus node dysfunction (SND) is commonly seen in patients with atrial fibrillation (AF). The purpose of this study was to compare the incidence of pacemaker implantation among patients with SND and AF treated with catheter ablation (CA) versus anti-arrhythmic drugs (AADs). METHODS: The 2013-2022 Optum Clinformatics database, an administrative claims database for commercially insured individuals in the United States (US), was used for this study. Patients with AF and SND and a history of at least one AAD prescription were identified and classified into CA or AAD cohorts based on subsequent treatment received. Inverse probability treatment weighting was applied to balance socio-demographic and clinical characteristics between the cohorts. Weighted Cox regression modeling was used to evaluate the differential risk of incident permanent pacemaker (PPM) implantation. Sub-analyses were performed by AF type (paroxysmal versus persistent). RESULTS: A total of 1206 patients in the AAD cohort and 1624 patients in the CA cohort were included. Study cohorts were well-balanced post-weighting. The incidence rate of PPM implantation (per 1000 person-year) was 55.8 for the CA cohort and 117.8 for the AAD cohort. Regression analysis demonstrated that the CA cohort had 42% lower risk of incident PPM implantation than those treated with AADs (hazard ratio [HR], 0.58; 95% CI, 0.46-0.72, p < 0.001). CA-treated patients had lower risks of PPM implantation versus AAD-treated patients among those with paroxysmal AF (HR, 0.48; 95% CI, 0.34-0.69, p < 0.001) and persistent AF (HR, 0.57; 95% CI, 0.40-0.81, p = 0.002). CONCLUSIONS: Patients with AF and SND treated with CA have significantly lower risks of incident PPM implantation compared with those treated with an AAD.

Hemodynamics and arrhythmia disorder caused by lithium poisoning: A case report. / 锂中毒导致心律失常、血流动力学障碍1例.

Bipolar affective disorder refers to a category of mood disorders characterized clinically by the presence of both manic or hypomanic episodes and depressive episodes. Lithium stands out as the primary pharmacological intervention for managing bipolar affective disorder. However, its therapeutic dosage closely approaches toxic levels. Toxic symptoms appear when the blood lithium concentration surpasses 1.4 mmol/L, typically giving rise to gastrointestinal and central nervous system reactions. Cardiac toxicity is rare but serious in cases of lithium poisoning. The study reports a case of a patient with bipolar affective disorder who reached a blood lithium concentration of 6.08 mmol/L after the patient took lithium carbonate sustained-release tablets beyond the prescribed dosage daily and concurrently using other mood stabilizers. This resulted in symptoms such as arrhythmia, shock, impaired consciousness, and coarse tremors. Following symptomatic supportive treatment, including blood dialysis, the patient's physical symptoms gradually improved. It is necessary for clinicians to strengthen the prevention and recognition of lithium poisoning.

Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction.

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.

Pericarditis prophylactic therapy after sinus node-sparing hybrid ablation for inappropriate sinus tachycardia/postural orthostatic sinus tachycardia.

Background: Pericarditis is the most common complication following hybrid sinus node-sparing ablation for inappropriate sinus tachycardia (IST)/postural orthostatic tachycardia syndrome (POTS). Objective: The study sought to evaluate the association of prophylaxis therapy on the risk of symptomatic pericarditis following hybrid IST/POTS ablation. Methods: All consecutive patients undergoing to hybrid ablation of symptomatic IST/POTS refractory or intolerant to drugs were retrospectively analyzed. Pharmacological prophylaxis therapy was based on acetylsalicylic acid and colchicine started on the day of the ablation and continued for at least 3 months. The primary endpoint was occurrence of symptomatic pericarditis. The secondary endpoint was occurrence of pericarditis-related complications, including the following: duration of pericarditis >3 months, hospitalization for pericarditis, postpericardiectomy pleuro-pericarditis, and pericardiectomy. Results: A total of 220 patients undergone to hybrid IST/POTS ablation were included and 44 (20%) underwent prophylaxis therapy. Pericarditis occurred in 101 (45.9%) patients, with 97 (96%) in the first 5 days. At survival analysis, prophylaxis was associated with higher rate of freedom from pericarditis (81.9% vs 47.2%, log-rank P < .001). Pericarditis-related complications were low, occurring in 7 (3.2%) patients. There was no difference in pericarditis-related complications between the patients who underwent prophylaxis therapy and patients who did not. At Cox multivariate analysis, predictors of pericarditis were IST (vs POTS) (hazard ratio 0.61, 95% confidence interval0.39-0.99, P = .04) and prophylaxis therapy (hazard ratio 0.27, 95% confidence interval 0.13-0.55, P < .001). Conclusion: In a large cohort of patients undergoing hybrid ablation for IST/POTS, a prophylaxis therapy with acetylsalicylic acid and colchicine was associated with a lower rate of symptomatic pericarditis.

Predictors of pacemaker requirement in patients receiving implantable loop recorders for unexplained syncope: A systematic review and meta-analysis.

BACKGROUND: 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. OBJECTIVE: We performed a systematic review and meta-analysis to identify risk predictors for PPM insertion in ILR recipients with unexplained syncope. METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

Incidental Arrhythmias During Atrial Fibrillation Screening With Repeat 7-Day Holter ECGs in a Hospital-Based Patient Population.

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.

A case of exaggerated exuberance: Iatrogenic atrioventricular block/intra-Hisian Wenckebach during conduction system pacing.

Isolated sinus node dysfunction with its pursuant long-term risk for atrioventricular (AV) conduction disease poses a unique dilemma for proponents of CSP due to paucity of imprimatur guidelines. In such scenarios, the risk and prognosis of iatrogenic AV block is not well elucidated but is a valid concern. We report a case where CSP was complicated by iatrogenic AV block and peculiarly the rare phenomenon of intra-Hisian Wenckebach.