Treatment Of Sick Sinus Syndrome Research Articles

Roles of MDA-LDL/OX-LDL/LOX-1 and TNF-α/TLR4/NF-κB Signaling Pathways in Myocardial Damage by Implantations of Cardiac Pacemakers in Elderly Patients.

Permanent pacemakers are an established treatment for sick sinus syndrome and high-grade atrioventricular block. Permanent cardiac pacemaker implantations may damage the myocardium. This study evaluated markers of myocardial injury, oxidative stress and inflammation in elderly patients with permanent pacemaker implantations. Various markers were measured at 1, 2, 3 and 4 months after permanent pacemaker implantations in elderly patients. The levels of high-sensitivity troponin T (hsTnT), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), malondialdehyde-modified low-density lipoprotein (MDA-LDL), oxidized low-density lipoprotein (OX-LDL), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) were increased in 2-month group compared with control and 1- month groups (P<0.001), and were further increased at 4-month group compared with 2- and 3- month groups after pacemaker implantations (P<0.001). Patients with dual-chamber pacemakers had higher levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB than patients with single chamber pacemakers (P<0.001). Patients who underwent the pacemakers with the active fixation leads had raised levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB compared patients with pacemakers using the passive fixation leads (P<0.001). Myocardial blood flows in 3-month and 4-month groups were lower than 1-month and 2-month groups (P<0.001). Levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB were elevated in elderly patients with permanent pacemaker implantations and the activations of oxidative stress and pro-inflammatory signalling pathways may be associated with myocardial damages and ischemia after pacemaker implantations in elderly patients.

Methylxanthine Derivatives in the Treatment of Sinus Node Dysfunction: A Systematic Review.

While the chronotropic effects of theophylline and aminophylline are well-known, their clinical application in the treatment of sinus node dysfunction has not been established in a review. The purpose of this systematic review is to evaluate the efficacy and safety of methylxanthines in the treatment of bradyarrhythmias associated with sinus node dysfunction. A systematic review was conducted in accordance with PRISMA guidelines on Embase, PubMed, MEDLINE, Cochrane Central, Web of Science, SciELO, Korean Citation Index, Global Index Medicus, and CINAHL through June 2023. A total of 607 studies were identified through the literature search. After applying the inclusion and exclusion criteria, 14 studies were included in this review. The causes of bradyarrhythmias involving the sinoatrial node included acute cervical spinal cord injury, coronavirus disease of 2019, carotid sinus syncope, chronotropic incompetence, heart transplant, and chronic sinus node dysfunction. Theophylline and aminophylline were shown to be effective for increasing heart rate and reducing the reoccurrence of bradyarrhythmias. The data on symptom resolution was conflicting. While many case studies reported a resolution of symptoms, a randomized controlled trial reported no significant difference in symptom scores between the control, theophylline, and pacemaker groups in the treatment of sick sinus syndrome. The incidence of adverse effects was low across all study designs. The data suggests methylxanthines may be useful as an alternative or bridge to nonpharmacologic pacing; however, dosing has yet to be established for various indications. Overall, methylxanthines proved safe and effective as a pharmacologic therapy for bradyarrhythmic manifestations of sinus node dysfunction.

Regularity of prescriptions for sick sinus syndrome based on latent structure combined with association rules

This study aims to mine the regularity of traditional Chinese medicine(TCM) prescriptions for sick sinus syndrome(SSS) and provide a reference for clinical syndrome differentiation and treatment. The relevant papers were retrieved from CNKI, Wanfang, VIP, and SinoMed with the time interval from inception to January 31, 2023. The relevant information from qualified papers was extracted to establish a library. Lantern 5.0 and Rstudio were used to analyze the latent structure and association rules of TCMs with the frequency ≥3%, which combined with frequency descriptions, were used to explore the rules of TCM prescriptions for SSS. A total of 192 TCM prescriptions were included, involving 115 TCMs with the cumulative frequency of 1 816. High-frequency TCMs include Aconiti Lateralis Radix Praeparata, Ginseng Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma, Astragali Radix, and Salviae Miltiorrhizae Radix et Rhizoma. The high-frequency medicines mainly had the effects of tonifying, releasing exterior with pungent-warm, and activating blood and resolving stasis. The analysis of the latent structure model yielded 13 hidden variables, 26 hidden classes, 8 comprehensive cluster models, and 21 core prescriptions. Accordingly, the common syndromes of SSS were inferred as heart-Yang Qi deficiency, heart-spleen Yang deficiency, heart-kidney Yang deficiency, Yang deficiency and blood stasis, both Qi and Yin deficiency and blood stasis, and Yin and Yang deficiency. The analysis of association rules predicted 30 strong association rules, among which Ginseng Radix et Rhizoma-Aconiti Lateralis Radix Praeparata had the highest support. SSS is a syndrome with Yang deficiency and Qi deficiency as the root causes and cold, phlegm, and stasis as the manifestations. The clinical treatment of SSS should focus on warming Yang and replenishing Qi, which should be supplemented with the therapies of activating blood and resolving stasis, warming interior and dissipating cold, or regulating Qi movement for resolving phlegm according to the patients' syndromes.

ß-tubulin contributes to Tongyang Huoxue decoction-induced protection against hypoxia/reoxygenation-induced injury of sinoatrial node cells through SIRT1-mediated regulation of mitochondrial quality surveillance

BackgroundTYHX-Tongyang Huoxue decoction has been used clinically for nearly 40 years. The ingredients of TYHX are Radix Astragali (Huangqi), Red Ginseng (Hongshen), Rehmannia Glutinosa (Dihuang), Common Yam Rhizome (Shanyao) and Cassia-bark-tree Bark (Rougui). Our previous experiments confirmed that TYHX can protect sinoatrial node cells. However, its mechanism of action is not completely understood yet. PurposeThe present study aimed to determine the protective effects of TYHX against Sinus node cell injury under hypoxic stress and elucidate the underlying mechanisms of protection. MethodsThrough RNA sequencing analysis and network pharmacology analysis, we found significant differences in mitochondrial-related genes before and after hypoxia-mimicking SNC, resolved the main regulatory mechanism of TYHX. Through the intervention of TYHX on SNC, a series of detection methods such as laser confocal, fluorescence co-localization, mitochondrial membrane potential and RT-PCR. The regulatory effect of TYHX on β-tubulin in sinoatrial node cells was verified by in vitro experiments. The mechanism of action of TYHX and its active ingredient quercetin to maintain mitochondrial homeostasis and protect sinoatrial node cells through mitophagy, mitochondrial fusion/fission and mitochondrial biosynthesis was confirmed. ResultsThrough RNA sequencing analysis, we found that there were significant differences in mitochondrial related genes before and after SNC was modeled by hypoxia. Through pharmacological experiments, we showed that TYHX could inhibit the migration of Drp1 to mitochondria, inhibit excessive mitochondrial fission, activate mitophagy and increase the mitochondrial membrane potential. These protective effects were mainly mediated by β-tubulin. Furthermore, the active component quercetin in TYHX could inhibit excessive mitochondrial fission through SIRT1, maintain mitochondrial energy metabolism and protect SNCs. Our results showed that protection of mitochondrial function through the maintenance of β-tubulin and activation of SIRT1 is the main mechanism by which TYHX alleviates hypoxic stress injury in SNCs. The regulatory effects of TYHX and quercetin on mitochondrial quality surveillance are also necessary. Our findings provide empirical evidence supporting the use of TYHX as a targeted treatment for sick sinus syndrome. ConclusionOur data indicate that TYHX exerts protective effects against sinus node cell injury under hypoxic stress, which may be associated with the regulation of mitochondrial quality surveillance (MQS) and inhibition of mitochondrial homeostasis-mediated apoptosis.

Prolonged Episode of Asystole in a Patient with Sick Sinus Syndrome: Case Report

Background: Sick sinus syndrome (SSS), also known as sinus node dysfunction (SND), is a disorder of the sinoatrial (SA) node caused by impaired pacemaker function and impulse transmission producing a constellation of abnormal rhythms. Sick Sinus Syndrome is a highly relevant clinical entity, being responsible for the implantation of the majority of electronic pacemakers worldwide. Case Summary: An 80-year-old patient with a recent diagnosis of atrial fibrillation after a syncopal attack, presented to our clinic complaining of new onset lightheadedness. Following a pre-syncopal attack in our clinic, extensive analysis was performed and showed no underlying causes for the light headedness. A 24-hour Holter monitoring was performed and demonstrated signs of sick sinus syndrome with unusually prolonged sinus pauses without an escape rhythm. Urgent correction with permanent dual chamber pacemaker was performed with an uneventful postoperative recovery. Discussion: In sick sinus syndrome, cessation of sinus rhythm (sinus arrest) for short intervals without an escape rhythm, or longer periods of pause with replacement of sinus rhythm by an atrial or junctional rhythm are commonly seen. However, recurrent prolonged ventricular asystolic episodes are infrequently encountered and an extremely rare cause of syncope. It is known that triggers like anaesthesia, certain drugs or epilepsy can unmask sinus node dysfunction, which then manifests as significant atrial dysrhythmias and “rarely” asystole but long asystolic episodes of such duration were never reported in the absence of any trigger in patients with sick sinus syndrome. Permanent pacemaker placement is the recommended treatment for sick sinus syndrome.

2021 PACES Expert Consensus Statement on the Indications and Management of Cardiovascular Implantable Electronic Devices in Pediatric Patients: Executive Summary.

2021 PACES Expert Consensus Statement on the Indications and Management of Cardiovascular Implantable Electronic Devices in Pediatric Patients: Executive Summary.

A Famous Chinese Prescription That Promotes Hcn4 Activity in Bone Marrow Mesenchymal Stem Cells is Shenfu Injection: Opinion

Sick Sinus Syndrome (SSS) refers to a group of heart rhythm disorders caused by problems relating to the sinus node. Currently, there is no effective treatment for SSS, and an electronic pacemaker is required to support heart function in SSS patients. However, electronic pacemakers are associated with several defects. For example, external magnetic noise commonly interferes, leading to complications. In addition, some patients, especially children with congenitals inoatrial node dysfunction, are not suitable subjects for pacemaker insertion. Therefore, the search for new therapeutic strategies for treating cardiovascular diseases has become imperative. Shenfu injection (SFI), a Chinese herbal medicine, is effective in improving bradyarrhythmia. However, the underlying mechanism of SFI's therapeutic effect remains elusive.

Clinical review of sick sinus syndrome and atrial fibrillation.

Sick sinus syndrome (SSS) is aset of diseases with abnormal cardiac pacing, which manifests as diverse cardiac arrhythmias, especially bradycardia. The clinical presentation is inconspicuous in the early stage, but with the progression of this disease, patients may present with symptoms and signs of end-organ hypoperfusion. As acommon result in the natural history of the disease, SSS coexisting with atrial fibrillation (AF) forms the basis of bradycardia-tachycardia syndrome. Age-related interstitial fibrosis is considered to be the common pathophysiological mechanism between SSS and AF. The combination of these diseases will adversely affect the condition of patients and the efficiency of subsequent treatment. Although the exact mechanism is not clear to date, the extensive structural and electrical remodeling of the atrium are considered to be the important mechanism for the occurrence of AF in patients with SSS. Pacemaker implantation is the first-line treatment for symptomatic patients with SSS and documented bradycardia history. In view of the adverse effects of AF on the treatment of SSS, researchers have focused on evaluating different pacing modes and algorithms to reduce the risk of AF during pacing. Catheter ablationmay also be used as an alternative second-line therapy for some patients with SSS and AF.

Zenglv Fumai Granule protects cardiomyocytes against hypoxia/reoxygenation-induced apoptosis via inhibiting TRIM28 expression.

Myocardial ischemia/reperfusion (MIR) injury, which occurs following acute myocardial infarction, can cause secondary damage to the heart. Tripartite interaction motif (TRIM) proteins, a class of E3 ubiquitin ligases, have been recognized as critical regulators in MIR injury. Zenglv Fumai Granule (ZFG) is a clinical prescription for the treatment of sick sinus syndrome, a disease that is associated with MIR injury. The present study aimed to investigate the effect of ZFG on MIR injury and to determine whether ZFG exerts its effects via regulation of TRIM proteins. In order to establish an in vitro MIR model, human cardiomyocyte cell line AC16 was cultured under hypoxia for 5 h and then under normal conditions for 1 h. Following hypoxia/reoxygenation (H/R) treatment, these cells were cultured with different ZFG concentrations. ZFG notably inhibited H/R-induced cardiomyocyte apoptosis. The expression levels of four TRIM proteins, TRIM7, TRIM14, TRIM22 and TRIM28, were also detected. These four proteins were significantly upregulated in H/R-injured cardiomyocytes, whereas their expression was inhibited following ZFG treatment. Moreover, TRIM28 knockdown inhibited H/R-induced cardiomyocyte apoptosis, whereas TRIM28 overexpression promoted apoptosis and generation of reactive oxygen species (ROS) in cardiomyocytes. However, the effects of TRIM28 overexpression were limited by the action of ROS inhibitor N-acetyl-L-cysteine. In addition, the mRNA and protein levels of antioxidant enzyme glutathione peroxidase (GPX)1 were significantly downregulated in H/R-injured cardiomyocytes. TRIM28 knockdown restored GPX1 protein levels but had no effect on mRNA expression levels. Co-immunoprecipitation and ubiquitination assays demonstrated that TRIM28 negatively regulated GPX1 via ubiquitination. In sum, the present study revealed that ZFG attenuated H/R-induced cardiomyocyte apoptosis by regulating the TRIM28/GPX1/ROS pathway. ZFG and TRIM28 offer potential therapeutic options for the treatment of MIR injury.

Inter/Intra-Atrial Dissociation in Patients With Maze Procedure and Its Clinical Implications: Pseudo-Block and Pseudo-Ventricular Tachycardia.

BackgroundSevere conduction delay and inter/intra‐atrial dissociation may occur in patients who undergo an extensive catheter ablation or a maze procedure for atrial tachyarrhythmia. We report a series of patients with inter/intra‐atrial dissociation that mimicked complete atrioventricular block or ventricular tachycardia.Methods and ResultsWe retrospectively reviewed the medical records of 7 patients who were referred for the evaluation of atrioventricular block (patients 1–6) or ventricular tachycardia (patient 7) that occurred after biatrial maze procedure and valvular surgery. During the electrophysiologic study, slow atrial or junctional escape rhythm dissociated from isolated atrial activity mimicked complete atrioventricular blocks. Intra‐atrial dissociation of the right atrium or left atrium was observed. Atrioventricular nodal conduction from the nondissociated atrium to the ventricle was preserved in all patients, while the conduction from the dissociated atrium was blocked. In patient 7, the pacing of the ventricle by tracking of atrial tachycardia from the nondissociated left atrium/coronary sinus mimicked ventricular tachycardia during pacemaker interrogation. A total of 5 patients received new permanent pacemaker implantations during the index hospitalization for the surgery (n=2) or as a deferred procedure (n=3) according to the treatment for sick sinus syndrome.ConclusionsPseudo‐atrioventricular block or pseudo‐ventricular tachycardia may occur because of inter/intra‐atrial dissociation after a maze procedure. The selection of patients for permanent pacemaker implantation should be determined based on the patient’s symptoms and the status of the escape pacemaker and not on the apparent atrioventricular block. Proper diagnosis is important to avoid unnecessary implantation of a pacemaker or a defibrillator.

Loss of Pacer Spikes as electrocardiographic (EKG) Artifact Due to Microdebrider Use During Endoscopic Dacryocystorhinostomy.

As intraoperative use of electronic equipment becomes more common, familiarity with the potential for electrocardiographic artifact generated by these instruments is increasingly important. The authors' patient underwent endoscopic dacryocystorhinostomy under general anesthesia for treatment of acute on chronic dacryocystitis secondary to acquired nasolacrimal duct obstruction. She had previously had pacemaker placement for treatment of sick sinus syndrome and low ejection fraction heart failure, and use of a microdebrider intraoperatively resulted in loss of pacer spikes and interference signal on electrocardiographic leading to placement of a magnet. Post-operatively, examination of the microdebrider cord revealed a tear that likely lead to the artifactual electrocardiographic signal influencing the decision for magnet placement. Although there were no long-term ill effects, placement of the magnet was an unnecessary intervention that may have been avoided by prompt recognition of artifactual changes that may be induced by intraoperative use of electronic instrumentation.

Exploration of Mahuang Fuzi Xixin Decoction formula syndromes based on severe cases of critical care and its application for nosocomial infection in critical care medicine including hyperpyrexia after tracheotomy and severe pain accompanied by acute myocardial infarction and diabetic peripheral neuropathy

Mahuang Fuzi Xixin Decoction recorded in Treatise on Febrile Diseases by Zhang Zhongjing in the Han Dynasty have been widely used in treating Yang deficiency and exogenous wind-cold syndrome by traditional Chinese medicine physicians for thousands of years. The indications of Mahuang Fuzi Xixin Decoction include bradyarrhythmia,sinus bradycardia,sick sinus node syndrome,senile exogenous,asthmatic cold,rhinitis,bronchial asthma,optic neuritis,optic atrophy,sudden blindness,sudden onset of cough,laryngeal obstruction,migraine,joint pain,low back pain,insomnia,shock,heart failure,renal failure,accompanied by fever or nosocomial infection,and hyperpyrexia after tracheotomy; dark complexion,chills,cold limbs,listlessness,fatigue,insomnia,lack of thirst,liking hot drinks,slightly swollen limbs or whole body,pale fat tongue,greasy fur,and deep pulse. Mahuang Fuzi Xixin Decoction is a potential drug for Shaoyin disease complicated with fever and pain. Tracheal intubation is an artificial ephedrine syndrome. It is necessary to distinguish Yin and Yang syndrome in treating hyperpyrexia after tracheotomy. However,it belongs to Yin syndrome,which could be treated by Mahuang Fuzi Xixin Decoction. Mahuang Fuzi Xixin Decoction is effective in the treatment of sick sinus syndrome,second degree atrioventricular block and third degree atrioventricular block. It can significantly alleviate symptoms,improve heart rate,and heart rhythm in a short period of time. However,after one year of drug withdrawal,the diseases may recur,indicating that Mahuang Fuzi Xixin Decoction may not improve the long-term prognosis of slow arrhythmia. Mahuang Fuzi Xixin Decoction is often used for fever or nosocomial infection in critical care medicine. In the treatment of critical care medicine complicated with high fever,Mahuang Fuzi Xixin Decoction is often taken continuously by stomach tube.

A new combination of transcription factors increases the harvesting efficiency of pacemaker‑like cells

Biological pacemakers that combine cell-based and gene-based therapies are a promising treatment for sick sinus syndrome or severe atrioventricular block. The current study aimed to induce differentiation of adipose tissue-derived stem cells (ADSCs) into cardiac pacemaker cells through co-expression of the transcription factors insulin gene enhancer binding protein 1 (ISL-1) and T-box18 (Tbx18). ADSCs were transfected with green fluorescent protein, ISL-1, Tbx18 or ISL-1+Tbx18 fluorescent protein lentiviral vectors, and subsequently co-cultured with neonatal rat ventricular cardiomyocytes in vitro for 7 days. The potential for regulating the differentiation of ADSCs into pacemaker-like cells was evaluated by cell morphology, beating rate, reverse transcription-quantitative polymerase chain reaction, western blotting, immunofluorescence and electrophysiological activity. ADSCs were successfully transformed into spontaneously beating cells that exhibited a behavior similar to that of co-cultured pacemaker cells. This effect was significantly increased in the combined ISL-1 and Tbx18 group. These results provide a potential strategy for enriching the cardiac pacemaker cell population from ADSCs.

The Effect of Astragaloside on Pacemaker Current and the Cytoskeleton in Rabbit Sinoatrial Node Cells Under the Ischemia and Reperfusion Condition.

Objective: We investigated the role of astragaloside in the treatment of sick sinus syndrome (SSS).Methods: Neonatal New Zealand rabbits were selected for the study. Rabbit sinoatrial node (SAN) cells were isolated by the method of dual enzymatic digestion and differential adherence. The injury model was prepared through simulated ischemia and reperfusion (I/R), and changes in the pacemaker current (If) were recorded using the whole-cell patch-clamp technique. The proteins F-actin and vinculin were examined between various groups of SAN cells using a microplate reader and laser scanning confocal microscopy. The mRNA level and protein expression of hyperpolarization-activated cyclic nucleotide gated potassium channel 4 (HCN4) were assessed by q-PCR and western blot method.Results: The peak current density of If was decreased to -19.64 ± 2.14 pA/pF in SAN cells after simulated I/R, and the difference was highly significant (P < 0.01). Following simulated I/R, 100, 200, or 300 μmol L-1 astragaloside was added to the extracellular solution of SAN cells; the peak current density of the If increased to -30.43 ± 1.98, -34.83 ± 1.6, and -52.72 ± 1.7 pA/pF, respectively (P < 0.01). Adding 100 μmol L-1 astragaloside to normal SAN cells also led to an enhanced peak current density of the If (P < 0.05). In a concentration-dependent manner, especially at 300 μmol/L, astragaloside was capable of increasing the expression of HCN4 and protecting the structural stability of F-actin and vinculin in the damaged SAN cells.Conclusion: We estimated that astragaloside could shorten the action potential duration 20 (APD20) and APD50 in damaged SAN cells of neonatal rabbits, thereby increasing the expression of HCN4 and the If current density in damaged SAN cells of neonatal rabbits in a voltage-dependent manner, accelerating the steady-state activation of the If channels, and protecting damaged cytoskeleton.

Complex regional pain syndrome induced by pacemaker implantation for sick sinus syndrome

A 53-year-old woman reported burning pain, muscle weakness, and dysesthesia of the left arm 2 months after permanent pacemaker insertion in the ipsilateral side for the treatment of sick sinus syndrome. Complex regional pain syndrome (CRPS) induced by pacemaker implantation was diagnosed. In 2017, her pulse generator became exhausted and was exchanged carefully to avoid exacerbation of CRPS, under the application of local anesthesia and premedication. Six months later, the patient's grip strength in her left hand remained lower relative to that in her right hand. Although rare, the presence of CRPS following device implantation should be remembered.

G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block.

Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies "sick sinus" syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca(2+) channels (Cav1.3(-/-)) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K(+) channel (IKACh) could rescue SSS and heart block in Cav1.3(-/-) mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3(-/-) mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3(-/-) mice or following selective inhibition of Cav1.3-mediated L-type Ca(2+) (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.

Generation of cardiac pacemaker cells by programming and differentiation

A number of diseases are caused by faulty function of the cardiac pacemaker and described as “sick sinus syndrome”. The medical treatment of sick sinus syndrome with electrical pacemaker implants in the diseased heart includes risks. These problems may be overcome via “biological pacemaker” derived from different adult cardiac cells or pluripotent stem cells. The generation of cardiac pacemaker cells requires the understanding of the pacing automaticity. Two characteristic phenomena the “membrane-clock” and the “Ca2+-clock” are responsible for the modulation of the pacemaker activity. Processes in the “membrane-clock” generating the spontaneous pacemaker firing are based on the voltage-sensitive membrane ion channel activity starting with slow diastolic depolarization and discharging in the action potential. The influence of the intracellular Ca2+ modulating the pacemaker activity is characterized by the “Ca2+-clock”. The generation of pacemaker cells started with the reprogramming of adult cardiac cells by targeted induction of one pacemaker function like HCN1–4 overexpression and enclosed in an activation of single pacemaker specific transcription factors. Reprogramming of adult cardiac cells with the transcription factor Tbx18 created cardiac cells with characteristic features of cardiac pacemaker cells. Another key transcription factor is Tbx3 specifically expressed in the cardiac conduction system including the sinoatrial node and sufficient for the induction of the cardiac pacemaker gene program. For a successful cell therapeutic practice, the generated cells should have all regulating mechanisms of cardiac pacemaker cells. Otherwise, the generated pacemaker cells serve only as investigating model for the fundamental research or as drug testing model for new antiarrhythmics. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Effectiveness of atrial versus atrioventricular pacing for sick sinus syndrome during long-term follow-up.

According to the current guidelines, atrioventricular (DDD) pacing is superior to atrial pacing (AAI) in the treatment of sick sinus syndrome (SSS). To compare outcomes of AAI and DDD pacing in patients with SSS during long-term follow-up. We studied 809 patients, including 86 patients in the AAI group (57 women, mean age 65 ± 15 years) and 723 patients in the DDD group (406 women, mean age 71.5 ± 10 years). Evaluation of outcomes of AAI and DDD pacing in SSS was based on the analysis of medical records of patients who underwent pacemaker implantation. Average duration of follow-up was 52 ± 25 months. In the AAI group, 63 of 86 patients remained without intervention. In the DDD group, 661 of 723 patients did not require surgical intervention. Overall, 105 patients died, including 13 in the AAI group and 92 in the DDD group (p = 0.4516). In the AAI group, a high degree atrioventricular block occurred on average after 46.3 ± 8.8 months and its incidence was estimated at 0.85% per year. Atrial fibrillation (AF) developed in 8 patients in the AAI group and 81 patients in the DDD group (p = 0.23). Among aetiological factors of an increased risk of developing AF, only the presence of tachycardia-bradycardia syndrome (hazard ratio [HR] 11.31) and the absence of antiarrhythmic therapy (HR 4.23) significantly increased the risk of AF. Urgent reoperation was needed in 23 patients in the AAI group and 62 patients in the DDD group (p < 0.01). Log-rank test analysis showed a significant effect of the development of AF on the risk of reoperation in this group (p = 0.0420). Lead-related complications were noted in 6 patients in the AAI group and 49 patients in the DDD group (p = 0.94). After 45 months, the risk of reoperation in the AAI group increased significantly due to a need for ventricular lead implantation. 1. Atrial stimulation is safe in SSS but it may be associated with an increased risk of ventricular lead implantation if atrioventricular block or persistent AF with slow ventricular rate develops. 2. DDD and AAI groups did not differ significantly in terms of survival, development of persistent AF, and lead-related complications. 3. Tachycardia-bradycardia syndrome and the lack of antiarrhythmic treatment with beta-blocker and amiodarone increased the risk of persistent AF during long-term follow-up. 4. A higher rate of reoperations in patients with AAI systems, related mainly to development of persistent AF, especially after the fourth year of follow-up, may justify DDD system implantation in SSS.

Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression

Although the right atrium (RA contains subsidiary atrial pacemaker (SAP) tissue that can take over from the sinoatrial node (SAN) in sick sinus syndrome (SSS), SAP tissue is bradycardic. Little is known about SAP tissue and one aim of the study was to characterize ion channel expression to obtain insight into SAP pacemaker mechanisms. A second aim was to determine whether HCN over-expression (a 'biopacemaker'-like strategy) can accelerate the pacemaker rate producing a pacemaker that is similar in nature to the SAN. SAP tissue was isolated from the rat and the leading pacemaker site was characterized. Cell size at the leading pacemaker site in the SAP was smaller than in the RA and comparable to that in the SAN. mRNA levels showed the SAP to be similar to, but distinct from, the SAN. For example, in the SAN and SAP, expression of Tbx3 and HCN1 was higher and Nav1.5 and Cx43 lower than in the RA. Organ-cultured SAP tissue beat spontaneously, but at a slower rate than the SAN. Adenovirus-mediated gene transfer of HCN2 and the chimeric protein HCN212 significantly increased the pacemaker rate of the SAP close to that of the native SAN, but HCN4 was ineffective. SAP tissue near the inferior vena cava is bradycardic, but shares characteristics with the SAN. Pacing can be accelerated by the over-expression of HCN2 or HCN212. This provides proof of concept for the use of SAP tissue as a substrate for biopacemaking in the treatment of SSS.

Efficacy of Catheter Ablation for Atrial Fibrillation in Patients with a Permanent Pacemaker for Sick Sinus Syndrome

To study the clinical efficacy of catheter ablation for paroxysmal atrial fibrillation (AF) in patients with a permanent pacemaker (PM) for sick sinus syndrome (SSS). Our prospectively established database of patients who underwent circumferential pulmonary vein (PV) ablation for paroxysmal AF was retrospectively reviewed. A total of 41 patients with a permanent PM for the treatment of SSS (SSS+PM group) and 123 age- and gender-matched control subjects (on a 1: 3 basis) without SSS or a permanent PM (no-SSS+no-PM group) were included in this study. AF recurrence was defined as the occurrence of confirmed atrial tachyarrhythmia lasting more than 30 seconds beyond three months after catheter ablation in the absence of any antiarrhythmic treatment. During a mean follow-up period of 18.3±10.6 months (range 3-30 months), 50 patients (30.5%) developed recurrence of AF. The recurrence rate was higher in the SSS+PM group than in the no-SSS+no-PM group (43.9% vs. 26.3%, p=0.011). A Cox regression analysis adjusted for age, valvular heart disease, left atrial (LA) diameter and PV isolation identified only SSS and the use of a PM together as an independent predictor of recurrence of AF (hazard ratio 2.02, 95% confidence interval 1.10-3.69, p=0.023). Patients with a permanent PM for SSS are at an increased risk of recurrence of AF after catheter ablation.