New Strategies for the Treatment of Sick Sinus Syndrome

Atsushi Morisue1, MD, PhD

1 The Center for Heart Development, State Key Lab of Development Biology of Freshwater Fish, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410006, China;
2 Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China.
# These authors contributed equally to this work
* Corresponding authors

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Xiushan Wu, PhD, Director and Professor, The Center for Heart Development, Hunan Normal University, Changsha, 410081, Hunan, China.
Email: xiushanwu2003@aliyun.com
Telephone: +86-0731-88872780

Received: Macrh 18, 2020
Revised: Macrh 31, 2020
Accepted: April 3 2020
Published online: April 17, 2020


Sick sinus syndrome (SSS) is an organic disorder of the sinoatrial node and its adjacent tissues, which causes problems in sinus node pacing function and sinus node conduction, thus leading to arrhythmias and multiple symptoms. The aetiology of the syndrome is complex, and the pathogenesis is unknown. Traditional therapies for SSS include drug therapy and pacemaker implantation, which have only partially succeeded clinically and cannot cure SSS. Hence, there is an urgent need to develop targeted therapies in order to treat SSS. This article aims to summarize the aetiology and pathogenesis of SSS, discuss the advantages and disadvantages of traditional treatment methods, and focus on the biological pacing strategies based on gene and cell therapy.

Key words: Sick sinus syndrome; Pathogenesis; Traditional therapy; Gene therapy

© 2020 The Authors. Published by ACT Publishing Group Ltd. All rights reserved.

Liu Y, Li Y, Zhu P, Zhuang J, Wu X. New Strategies for the Treatment of Sick Sinus Syndrome. Journal of Cardiology and Therapy 2020; 7(1): 913-921 Available from: URL: http: //www.ghrnet.org/index.php/jct/article/view/2837


Sick sinus syndrome (SSS), also known as sinus node dysfunction (SND), includes sinus arrest, sinoatrial block, bradycardia and tachycardia and other arrhythmia manifestations. The syndrome occurs at all ages, including newborns, with the highest incidence among people aged over 65 years. Previous population studies have shown that older adults are at increased risk of SSS[1-3]. At present, SSS remains an incurable and progressive disease. Traditional treatment methods include drug therapy and nondrug therapy. Drug therapy includes the use of western medicine and traditional Chinese medicine to stabilize the heart rate. Nondrug therapy mainly involves the use of electronic pacemaker implantation. This article aims to summarize the aetiology and pathogenesis of SSS, discuss the advantages and disadvantages of traditional treatment methods, and focus on the biological pacing strategies based on gene and cell therapy.

Clinical manifestations and aetiology

1. Clinical manifestations

The onset of SSS is insidious, and the course of development is mostly slow. It can take 5-10 years or even longer from the onset of symptoms to severe symptoms. The main clinical manifestation of SSS is bradycardia; as the disease progresses, cardiogenic cerebral ischaemic syndromes can appear, such as dizziness, darkening or syncope, and even SSS or sudden death. Cardiac abnormalities are characterized by palpitations, congestive heart failure and angina pectoris, and these three major cardiac symptoms are interrelated. Oliguria, loss of appetite and muscle soreness also occur[2].

1.2. Aetiology

SSS is not caused only by a single factor. Different pathophysiological mechanisms can cause similar disease phenotypes. Table 1 lists the causes of SSS. The causes of SSS are both endogenous and exogenous. Endogenous causes include sinoatrial node (SAN) degenerative fibrosis, coronary heart disease, cardiomyopathy, myocarditis, pericarditis, hypertension, invasive disease and congenital heart disease. Exogenous causes include drug effects (β-receptor blockers, calcium antagonists, digoxin and antiarrhythmic drugs), vagus nerve tension, electrolyte disturbance, surgical injury, hypothyroidism and increased intracranial pressure[4-9]. The endogenous aetiology is usually irreversible; once it occurs, an electronic pacemaker is usually implanted. However, some exogenous causes of SSS are reversible. For example, the symptoms can be improved by discontinuing the patients’ medication. SSS can also be familial, and mutations in genes such as HCN4, SCN5A, MYH6 and CACNA1C can cause SSS[10-14].

Table 1 Causes of Sick Sinus Syndrome.
Degenerative fibrosisPharmacologic agentsFamilial SSS
AgingDigitalisSCN5A, HCN4, MYH6, CACNA1C
Atrial tachyarrhythmiasDigoxin 
Associated with atrial myopathyβ-Blockers 
AmyloidosisCalcium channel blockers 
Connective tissue diseasesAntiarrhythmics 
Hereditary muscle dystrophiesClonidine, methyldopa, reserpine 
MyocarditisLithium, phenothiazine, amitriptyline 
Valvular heart diseaseMetabolic disorders 
Heart failureHyperkalemia 
Obstructive sleep apneaAcute ischemia 
Pediatric causesSurgical injury 
Congenital abnormalities  
Sinoatrial nodal artery deficiency  
Rheumatic fever  
Chagas disease  

Traditional treatment

SSS has no standard treatment. The clinical treatment principle is to accurately determine the cause of this condition and treat it symptomatically. For patients with SSS, the cause should be identified and corrected, the normal function of the sinus node should be restored, and further development of the disease should be prevented. There are two main types of clinical treatment for SSS: drug therapy and pacemaker implantation.

1. Drug treatment

At present, there is no clinical consensus on the optimal medication regimen for SSS. Therefore, drug treatment is often difficult, it lacks long-term therapeutic effects, and various antiarrhythmic drugs often have significant and intolerable side effects. It is necessary to determine the timing of treatment, control the dose of the medication, and avoid using medications that can slow down the heart rate (such as β-blockers, verapamil, digitalis and other drugs) during drug treatment. For patients with mild SSS, no special treatment is needed; only regular follow-up observations are required[15]. When the patient develops bradycardia and obvious symptoms, conventional drugs (such as atropine, aminophylline, isoprenaline and nicotinyl) can be used to increase the heart rate. Intravenous atropine and β-stimulants, although effective in the short term, are harmful when used long term. Their side effects include cardiotoxicity and ventricular arrhythmias[16]. For patients with slow-fast syndrome, it is difficult to manage the bradycardia and tachycardia. Digitalis can be used in small doses when necessary to prevent or reduce the occurrence of tachyarrhythmia. Small doses of digitalis do not affect the sinus node and the atrioventricular conduction system. For neonatal patients in whom immediate implantation of a pacemaker is difficult, the results of a recent study[17] suggest that procaterol is an effective treatment for infants and young children with SSS. After the diagnosis of SSS, medications were administered to the baby boy in a forementioned study through the gastrointestinal enteral route. The patient’s condition was well controlled, and pacemaker implantation was no longer required. Cilostazol is effective for the treatment of symptomatic SSS and can stabilize the condition by increasing the heart rate, thereby preventing the need for permanent pacemaker implantation[18]. In Japan, cilostazol has been widely accepted for the clinical treatment of bradycardia[19]. In addition, traditional Chinese medicine and decoction treatment, and acupuncture and other methods have increasingly been recognized in clinical practice because of their significant effects and few adverse effects[20]. Shenxian-shengmai oral liquid is a kind of Chinese patent medicine that is used in the treatment of patients with mild SSS[21-24]. Traditional Chinese medicine research studies have shown that ginsenoside and calcium dibutyryladenosine can effectively treat SSS[25]. Although the efficacy of traditional Chinese medicine, acupuncture and other treatment methods in improving sinus node function was only reported in clinical studies, these methods were still applied in the clinical setting and was proven to be effective. However, pharmacological research on the drug and its mechanism of action are still in a fuzzy state.

2. Pacemaker implantation

Since the use of electronic pacemakers in the clinical setting[26-27], several patients’ lives have been saved. Permanent pacemaker implantation is currently the only effective treatment for SSS and the most common cause of pacemaker implantation[28-29]. The pacemaker’s battery is usually placed in the subcutaneous tissue of the chest or abdomen, and works through pulse generators and electrode wires[20]. Despite the success in the use of electronic pacemakers, there are still disadvantages that cannot be ignored, including inability to adjust autonomously, limited battery life, lead displacement, possibility of infection and bleeding, and vulnerability to electromagnetic interference. Moreover, the use of pacemakers in paediatric patients remains a challenge[26,30-32].

There has been controversy regarding the choice of pacemaker mode (single-chamber atrial pacing (AAIR) or dual-chamber pacing (DDDR)) in patients with SSS. Owing to the development of pathological SSS, atrioventricular block and atrial fibrillation are common. Although a large number of studies have reported the advantages of single-chamber atrial pacing in patients with SSS, this method is rarely used. In daily clinical practice, because of the fear of high atrioventricular block after pacemaker implantation, in order to improve the prognosis, most patients with SSS choose a conventional dual-chamber pacemaker. Does every SSS patient need a dual-chamber pacemaker? Is it more reasonable to choose a dual-chamber pacemaker (DDDR) or a single-chamber pacemaker (AAI)? The DANPACE study is a multicentre randomized study conducted in Denmark. A total of 1,415 patients with SSS were randomly divided into an AAIR group and a DDDR group. The average follow-up was 5.4 ± 2.6 years. The results suggest that for SSS patients, when there is no significant difference in all-cause mortality when receiving AAIR and DDDR treatment, DDDR treatment should be preferred to reduce the risk of atrial fibrillation and re-pacing[33]. However, recent studies[34] have shown that AAIR pacing should be considered in patients with SSS without atrioventricular block. Therefore, for patients with SSS who require a permanent pacemaker implantation, an appropriate pacing method should be selected after the intracardiac electrophysiological examination. Patients who receive a permanent pacemaker are at a higher risk for atrial fibrillation; hence, frequent pacemaker examinations should be performed. Patients with a history of atrial fibrillation should also be assessed for the risk of stroke and bleeding, and make informed decisions about the use of anticoagulants.

New treatment strategies

Drugs and electronic pacemakers have only achieved partial success in treating sick sinus syndrome. At present, there is an urgent need to develop targeted therapies based on pathogenesis to treat sick sinus syndrome. Recent studies have explored the feasibility and applicability of biological pacing, demonstrating the potential utility of gene- and cell-based therapy for sick sinus syndrome[35-40]. SAN is the main pacemaker of the heart, and SSS is associated with structural and functional abnormalities of SAN. A better understanding of the genes that regulate the development and function of SAN is essential for the development of biological pacemakers. Therefore, before introducing biological pacing strategies, we first introduce tissue and organ lesions and the relationship between gene regulation and disease occurrence.

1. Tissue and organ diseases

SAN is the main pacemaker of the heart. It is located at the junction of the superior vena cava and the right atrium. It is centred on the SAN artery and can regulate the heart’s beating frequency[41]. SAN includes the head, centre, tail, peripheral areas and several sinus node conduction pathways (SACPs). The ‘guide pacemaker’ site, the first activated site of SAN, is usually located in the central part of SAN, and SACPs are considered to be the preferential conduction pathway of electrical impulses from SAN to the atrial myocardium[42-45] (Figure 1). Sinus pacing and conduction abnormalities can cause arrhythmias, and sick sinus syndrome is associated with structural and functional abnormalities of SAN.

Figure 1 SAN is a multicompartment structure, composed of a head / centre and tail / periphery region, and several specialized conduction pathways. The schematic above represents 3D reconstruction of SAN (blue) with five SACPs (yellow). Modified from[44].

A mature SAN is composed of different types of cells, including cardiac pacing cells and a large number of nonpacing cells. Pacing cells are usually assigned into clusters surrounded by fibroblasts and a variable extracellular matrix (fibrous tissue). When the SAN pacing cells are gradually replaced by fibrous tissue, the number of pacing cells will decrease, and their normal pacing function will gradually decrease[55,46-47]. With age, the increase in pathological fibrosis in SAN and SACPs interrupts the tight coupling between SAN myocardial cells and affects the interconnections between cells, which is essential for the stable pacing of SAN. This will usually result in bradycardia and conduction block. Sinus node fibrosis is involved in the pathogenesis of SSS[3]; SAN tissue fibrosis affects the generation and conduction of SAN action potentials, leading to SSS[5,48]. The transient receptor potential cation channel M7 (TRPM7) is associated with cardiac fibrosis. Zhong et al[49] found that SAN fibrosis is regulated by the Ang II/TRPM7/Smad pathway in SSS. TRPM7 is a potential target for sinus node fibrosis treatment in SSS.

Changes in connexin expression in the SAN region accompanied by ageing are also associated with SND[5]. Connexins form gap junctions between adjacent cells and play an important role in pulse propagation between cells and even throughout the heart[50]. Compared with atrial tissues, several key ion channel protein subtypes were expressed in human SAN with a higher expression of connexin Cx43. This uneven expression promotes its autonomy and protects it from arrhythmias[7,44]. In the course of cardiac surgery, when SAN or surrounding tissue is directly damaged, an abnormal sinus node function can occur after surgery and cause arrhythmia. Heart disease or immune disease may cause the SAN cells to gradually die due to ischaemia and hypoxia, eventually leading to the decline in SAN function and thus SSS[51].

2. Gene regulation and disease occurrence

2.1. Transcription factors and SSS

The abnormal development of SAN will lead to the occurrence of SSS. Transcription factors related to the development of SAN include Tbx18, Tbx3, Shox2, Isl1, Nkx2-5, and Pitx2[45,52-58]. Tbx18 is an important transcription factor during embryonic development and plays an important role in the formation and development of SAN. Tbx18 controls SAN head formation, but Tbx18 deletion does not affect tail development. Tbx3 is also expressed in SAN. During heart development, Tbx3 is essential for pacemaker and conduction system development[59]. During Tbx18 controlling head formation, Tbx3 further regulates the pacing gene program. Shox2 is involved in the differentiation of pacing cells. During cardiac development, Shox2 loss can cause sinus node developmental disorders, which is manifested by bradycardia. Shox2 works by inhibiting Nkx2-5 and simultaneously activating Isl1 expression. The transcription factor Isl1 plays a role downstream of Shox2, is necessary for SAN premise cell proliferation, and is expressed in both embryonic and adult SAN[60-61]. Under normal circumstances, SAN is developed unilaterally, and Pitx2 directly inhibits the expression of Shox2 and upregulates two microRNAs that can inhibit the expression of the SAN gene[58]. In Pitx2-deficient embryos, SAN develops bilaterally[24]. The formation of SAN is strictly regulated by a network of transcription factors. These transcription factors present a dynamic and unique expression pattern in the working myocardium of SAN and its surrounding atria, in the differentiation and specialization of pacemaker cells, and in maintaining pacemaker characteristics and functions. However, under physiological and pathological conditions, the role of these pacemaker-specific transcription factors in the structural and functional homoeostasis of adult SAN still needs to be explored in more detail[45].

2.2. Ion channel-related genes and SSS

The hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) is a kind of cyclic superfamily cation channel. This channel plays an important role in regulation of the special current existing in the SAN pacing—If (funny current)[44,62]. When the SAN tissue, or other heart tissue lesions containing HCN channel subtypes, is damaged, the HCN channel subtypes are abnormally expressed, failing to form If currents and eventually leading to arrhythmias[63]. There are four subtypes of HCN channels (HCN1–4). HCN1, HCN2 and HCN4 are expressed in mammalian hearts, of which HCN4 is the most important and most widely expressed, accounting for about 75% of If in SAN[11,64-65]. HCN4 is the main channel subtype of If that maintains the normal pacing current of the heart, and its deletion (heterozygous or homozygous) can cause embryonic pacing cells to fail or mature[66]. Induction of HCN4 knockout later in life in mice can lead to severe bradycardia and conduction system disease, suggesting that the gradual loss of HCN4 channel function over time may contribute to the development of SSS[67]. Previous studies have reported several mutations in the HCN4 gene, and these mutations affect the normal expression of HCN4 protein, leading to familial SSS[63,68-73].

The voltage-gated sodium channel (Nav) and the INa current generated play an important role in the promotion of membrane potential depolarization. Among them, the SCN5A gene encoding the α-subunit of the Nav1.5 ion channel has been extensively studied, because it plays a key role in cardiac excitability. This gene mutation is related to a variety of human diseases and often causes severe arrhythmias, including atrial fibrillation, premature beats and SND[74]. So far, a large number of studies have found that the SCN5A gene mutations can trigger human SSS[75-78].

In addition, the L-type calcium channel current (ICa, L), which relies on the formation of L-type calcium ion channels, can be transmitted to all regions of the heart and is an extremely important inward current during the diastole of SAN cells. In SAN, Cav1.2 and Cav1.3-type calcium channels play an important role[11,79]. The gene mutations in the calcium channel subunits CACNA1D and CACNA1C can cause SSS[12,80].

2.3. MicroRNA and SSS

MicroRNA (miRNA) is an endogenous, short, noncoding RNA that mediates gene silencing at the post-transcriptional level[81]. miRNAs can cause a variety of diseases, including heart failure, myocardial hypertrophy and myocardial infarction[82-83], all of which may increase the susceptibility to SSS. For example, miR-17-92 and miR-106b-25, which are positively regulated by the transcription factor Pitx2, can directly target the inhibition of Shox2 and Tbx3 genes, which can promote SAN cell differentiation. In animal experiments, SND was found in both heart-specific knockout miR-17-92 mice and miR-106b-25 heterozygous mice[58]. miRNAs can regulate cardiac ion channel gene expression at the post-transcriptional level[84-85]. Recent research[79] has found that miRNA-1976 can play an important role in SAN ageing by targeting Cav1.2- and Cav1.3-type calcium channels. Therefore, miRNA-1976 is a potential noninvasive diagnostic tool and therapeutic target for SSS.

3. Biological pacing therapy

3.1. Biopacing based on gene therapy

Gene biopacing refers to the use of genetic engineering technology to introduce the target gene into the damaged autonomic rhythm point or the tissue of the conduction system. By introducing the gene to express the corresponding protein or inhibit the expression of certain genes in the body, the normal cardiac pacing or conduction function will be restored.

Pacing-like cells can be induced by transcription factor recoding[86-88]. For example, the TBX18 gene, which is essential for the development of the SAN head, is an important gene that can induce the production of pacing-like cells. Kapoor et al. [87] demonstrated the transformation of rodent cardiomyocytes into SAN cells in vitro and in vivo through the expression of TBX18. TBX18 was overexpressed in adult guinea pig myocardium, and transfected cardiomyocytes showed morphological and electrophysiological characteristics of SAN cells. Hu et al[89] used a minimally invasive method to inject a viral vector carrying TBX18 into a pig heart to develop a ‘biological pacemaker’ that can treat heart rhythm abnormalities, and they proved that the pacemaker is sufficient to support daily life needs. Overexpression of the TBX18 gene enhances the function of the atrial pacemaker in SSS rats, suggesting that the gene therapy targeting TBX18 may be integrated in human sick sinus nodes[90,91]. The pacemaker function was restored in the affected patient, thereby avoiding the need for an electronic pacemaker. Bakker et al[86] constructed Tbx3-overexpressing mice and isolated adult mouse cardiomyocytes for analysis. They found that the working myocardium had effectively transformed into pacemaker cells, and the expression of related genes encoding connexin and cardiac sodium channels was all suppressed. Although the results of reprogramming based on transcription factors are encouraging, two points are worth noting: one is the heterogeneity and the other is the limited duration of the phenotype after successful reprogramming. However, these problems may be solved by the long-term overexpression of nonimmunogenic vectors such as the adeno-associated virus AAV.

Biological pacing can be achieved by overexpressing ion channel-related genes in vivo[92,93]. For example, the role of HCN channel overexpression in the myocardium has been widely studied as a biological pacemaker strategy with some success[35,94,95]. Morris[96] and others found that the use of adenovirus-mediated overexpression of HCN2 and HCN212 genes can accelerate the pace of atrial-assisted pacemakers. This study provides theoretical proof for a new biological pacing strategy. The approach will help treat bradycardia in patients with SSS.

3.2. Cell-based biopacing

Cell-based artificial biological pacemakers can use stem cells to induce pacing-like SAN cells. They can be divided into embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) according to their source. In addition, cell therapy methods include the use of cells as a delivery tool for gene construction[97,98]. At present, gene transfection vectors mainly include adenovirus, adeno-associated virus, lentivirus, liposome and electroporation. Among them, the most commonly used is adenovirus.

ESCs and iPSCs can differentiate into cardiomyocytes, can show intrinsic pacemaker activity, and can pace ventricular muscle in vivo[99-102]. Mummery et al[103] used human ESCs to induce differentiation in the cardiac muscle tissue with pacing function. Zhu et al[104] found that the intervention of the NRG-1β/ErbB signalling pathway in ESCs can increase the expression of Tbx3, thereby increasing the expression of sinus node-related genes, promoting the differentiation of stem cells into sinus node-like cells, and detecting sinus node-like action potential. However, the application of ESCs in clinical practice is facing ethical issues; hence, their clinical application is limited. iPSCs have pluripotency similar to ESCs, and their differentiation potential is similar to ESCs. The method used to obtain them is relatively simple and stable. They can be obtained from autologous cells without the need for egg cells or embryos. This prevents immune rejection and ethical controversies in cell transplantation. Spontaneous beating cells are present in iPSC-derived cardiomyocytes (iPSC-CMs), and diastolic depolarization potentials and genes associated with sinus node characteristics can be detected[105,106]. Recent studies[107] have found that TBX3 can induce pacing function in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). However, TBX3 overexpression alone is not enough to cause the diastolic depolarization of hiPSC-CMs, whereas the simultaneous overexpression of TBX3 and HCN2 can successfully re-encode hiPSC-CMs into pace-like cells and cause diastolic depolarization. This provides a new strategy for building biological pacemakers.

MSCs are pluripotent stem cells with promising prospects in the field of regenerative medicine. This and other studies have shown that overexpressing human genes such as pygo2 with Nkx2.5 to promote the differentiation of human umbilical cord MSCs into cardiomyocytes is a better method to obtain cardiomyocytes[108-109]. Other studies have shown[110] that 5-azacytidine-induced bone marrow MSCs can differentiate into pacemaker-like cells that express HCN2 channel proteins and If currents. In addition to chemical induction, microenvironment induction can be adopted. The microenvironment induction method is safer and prevents the risk of cytotoxicity and mutagenicity. Wang et al[111] found that bone marrow MSCs can interact with cardiomyocytes and express connexins Cx40 and Cx43, forming gap junctions and open HCN channels, generating pacing function, and maintaining stability for a long time. MSCs can be obtained in vivo; are easy to isolate, purify, expand and culture, without the risk for immune rejection and ethical issues; and easy to integrate foreign genes. At present, most studies have used MSCs as a carrier, and transfection pacemaker genes or transcription factors that regulate the differentiation of SAN obtain sinus node-like cells that can express the pacing gene to produce current characteristics. MSCs have become the ideal carrier cells for the biological pacing treatment of SSS. Yang et al[112] used the HCN4 lentiviral vector to transfect MSCs, the pacing-like cells expressed the typical pacing protein HCN4, and the whole patch clamp detected a typical pacing current If.


At present, neither the medical treatment nor the implantation of artificial pacemakers can cause physiological or pathological changes to the heart. The development of a biological pacing treatment strategy brings new hope for the cure of SSS patients; however, there are still other techniques of using biological pacing in clinical practice. Several issues such as the selection of biological pacing target genes, a safe, effective and controllable in vivo gene delivery system, and the safety of stem cells have not been completely resolved. The replacement of electronic pacemakers by biological pacemakers is still the direction of future development. Hence, researchers should continue to use various animal models for experimental research in the molecular field, explore the pathogenesis of new SSS, and improve their understanding of the pathogenesis of SSS in order to discover new therapeutic targets. In the near future, through continuous research, biological pacemakers can be safely and effectively used in the treatment of patients with SSS. To date, electronic pacemakers remain the only effective treatment for SSS. Before biological pacemaker therapy is successfully applied in the clinical setting, older adults should take precautions according to their cause of illness. Moreover, prognosis management should be implemented in sick people.


This study was supported in part by grants from the National Natural Science Foundation of China (grant nos. 81670290, 81470449, 81570279, 81974019), the Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province (grant no. 2013-448-6), National Key R&D Program of China (grant nos. 2018YFC1002600, 2018YFA0108700 and 2017YFA0105602), NSFC Projects of International Cooperation and Exchanges (grant no. 81720102004), The Research Team Project of Natural Science Foundation of Guangdong Province of China (grant no. 2017A030312007 ), Science and Technology Planning Projects of Guangdong Province of China (grant nos. 2017A070701013, 2017030314109, 2018B090944002, 2019B020230003 ), the Special Project of Dengfeng Program of Guangdong Provincial People’s Hospital (grant no. DFJH201802 ), the Key Program of Guangzhou Science Research Plan (grant no. 805212639211).


1. Dobrzynski H, Boyett MR, Anderson RH. New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation. 2007 Apr 10; 115(14): 1921-32. [PMID: 17420362]; [DOI: 10.1161/CIRCULATIONAHA.106.616011].

2. Adán V, Crown LA. Diagnosis and treatment of sick sinus syndrome. Am Fam Physician. 2003 Apr 15; 67(8): 1725-32. [PMID: 12725451].

3. Jensen PN, Gronroos NN, Chen LY, Folsom AR, deFilippi C, Heckbert SR, Alonso A. Incidence of and risk factors for sick sinus syndrome in the general population. J Am Coll Cardiol. 2014 Aug 12; 64(6): 531-8. [PMID: 25104519]; [DOI: 10.1016/j.jacc.2014.03.056].

4. Richardson L. Sick sinus syndrome. JAAPA. 2017 Jul; 30(7): 50-51. [PMID: 28644224]; [DOI: 10.1097/01.JAA.0000520546.61570.b5].

5. Csepe TA, Kalyanasundaram A, Hansen BJ, Zhao J, Fedorov VV. Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction. Front Physiol. 2015 Feb 12; 6: 37. [PMID: 25729366]; [DOI: 10.3389/fphys.2015.00037].

6. Monfredi O, Dobrzynski H, Mondal T, Boyett MR, Morris GM. The anatomy and physiology of the sinoatrial node--a contemporary review. Pacing Clin Electrophysiol. 2010 Nov; 33(11): 1392-406. [PMID: 20946278]; [DOI: 10.1111/j.1540-8159.2010.02838.x].

7. Makhaly S, Fallah P, Giannetti N. Elevated Intracranial Pressure as a Cause of Sick Sinus Syndrome. Case Rep Cardiol. 2018 Jun 3; 2018: 5015840. [PMID: 29967700]; [DOI: 10.1155/2018/5015840].

8. De Ponti R, Marazzato J, Bagliani G, Leonelli FM, Padeletti L.Sick Sinus Syndrome. Card Electrophysiol Clin. 2018 Jun; 10(2): 183-195. [PMID: 29784479]; [DOI: 10.1016/j.ccep.2018.02.002].

9. Jabbour F, Kanmanthareddy A. Sinus Node Dysfunction. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020-.2019 Jun 23. [PMID: 31334973].

10. Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George AL Jr. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003 Oct; 112(7): 1019-28. [PMID: 14523039]; [DOI: 10.1172/JCI18062].

11. Monfredi O, Boyett MR. Sick sinus syndrome and atrial fibrillation in older persons - A view from the sinoatrial nodal myocyte. J Mol Cell Cardiol. 2015 Jun; 83: 88-100. [PMID: 25668431]; [DOI: 10.1016/j.yjmcc.2015.02.003].

12. Zhu YB, Luo JW, Jiang F, Liu G. Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations. Mol Med Rep. 2018 May; 17(5): 7073-7080. [PMID: 29568937]; [DOI: 10.3892/mmr.2018.8773].

13. Holm H, Gudbjartsson DF, Sulem P, Masson G, Helgadottir HT, Zanon C, Magnusson OT, Helgason A, Saemundsdottir J, Gylfason A, Stefansdottir H, Gretarsdottir S, Matthiasson SE, Thorgeirsson GM, Jonasdottir A, Sigurdsson A, Stefansson H, Werge T, Rafnar T, Kiemeney LA, Parvez B, Muhammad R, Roden DM, Darbar D, Thorleifsson G, Walters GB, Kong A, Thorsteinsdottir U, Arnar DO, Stefansson K. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Genet. 2011 Mar 6; 43(4): 316-20. [PMID: 21378987]; [DOI: 10.1038/ng.781].

14. Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N.Novel mutation in the α-myosin heavy chain gene is associated with sick sinus syndrome. Circ Arrhythm Electrophysiol. 2015 Apr; 8(2): 400-8. [PMID: 25717017]; [DOI: 10.1161/CIRCEP.114.002534].

15. Wung SF. Bradyarrhythmias: Clinical Presentation, Diagnosis, and Management. Crit Care Nurs Clin North Am. 2016 Sep; 28(3): 297-308. [PMID: 27484658]; [DOI: 10.1016/j.cnc.2016.04.003].

16. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, Kudenchuk PJ, Ornato JP, McNally B, Silvers SM, Passman RS, White RD, Hess EP, Tang W, Davis D, Sinz E, Morrison LJ. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010 Nov 2; 122(18 Suppl 3): S729-67. [PMID: 20956224]; [DOI: 10.1161/CIRCULATIONAHA.110.970988].

17. Nakajima J, Mizutani K. Procaterol for Infantile Sick Sinus Syndrome. Indian Pediatr. 2019 Apr 15; 56(4): 336. [PMID: 31064913].

18. Sonoura T, Kodera S, Shakya S, Kanda J. Efficacy of cilostazol for sick sinus syndrome to avoid permanent pacemaker implantation: A retrospective case-control study. J Cardiol. 2019 Oct; 74(4): 328-332. [PMID: 30982679]; [DOI: 10.1016/j.jjcc.2019.03.007].

19. Yamashita S, Miyagawa K, Inagaki T, Dohi Y. Cilostazol increased heart rate with improvement of activity of daily living in an elderly patient with sick sinus syndrome. Nihon Ronen Igakkai Zasshi. 1999 Aug; 36(8): 561-4. [PMID: 10554564]; [DOI: 10.3143/geriatrics.36.561].

20. Cai WW, Zhu P, Yuan WZ, Wu XS. New Strategies for Arrhythmia Treatmen. Journal of Cardiol Ther. 2018 Dec; 5(1): 756-761. [DOI: 10.17554/j.issn.2309-6861.2018.05.162].

21. Zhao Y, Zhang X, Luan J, Zhao B, An N, Sun N, Wang X, Zhao T, Sun Y, Fu ZD, Zhang Y, Zhang Y. Shenxian-Shengmai Oral Liquid Reduces Myocardial Oxidative Stress and Protects Myocardium from Ischemia-Reperfusion Injury. Cell Physiol Biochem. 2018; 48(6): 2503-2516. [PMID: 30121659]; [DOI: 10.1159/000492688].

22. Hu JH, Chen SJ, Hua XL. Clinical research of Shenxianshengmai oral liquid in the treatment of sick sinus syndrome and sinus bradycardia. Chin Tradition Patent Med 2012; 34: 7-9.

23. Li P, Zeng L. Clinical observation of Shenxian-shengmai oral liquid in the treatment of bradycardia. Chin J Integr Med Cardio 2011; 9: 1121-1122.

24. Tang H, Li J, Huang ZH. Clinical observation on treatment of sick sinus syndrome with Shenxianshengmai oral liquid. Chin Med 2010; 5: 979-980.

25. Faggioni M, Savio-Galimberti E, Venkataraman R, Hwang HS, Kannankeril PJ, Darbar D, Knollmann BC. Suppression of spontaneous ca elevations prevents atrial fibrillation in calsequestrin 2-null hearts. Circ Arrhythm Electrophysiol. 2014 Apr; 7(2): 313-20. [PMID: 24493699]; [DOI: 10.1161/CIRCEP.113.000994].

26. Boink GJ, Christoffels VM, Robinson RB, Tan HL. The past, present, and future of pacemaker therapies. Trends Cardiovasc Med. 2015 Nov; 25(8): 661-73. [PMID: 26001958]; [DOI: 10.1016/j.tcm.2015.02.005].

27. Caloian B, Sitar-Taut AV, Gusetu GN, Pop D, Zdrenghea DT. The Influence of Cardiac Pacemaker Programming Modes on Exercise Capacity. In Vivo. 2018 Mar-Apr; 32(2): 419-424. [PMID: 29475931]; [DOI: 10.21873/invivo.11256].

28. Yang B, Huang Y, Zhang H, Huang Y, Zhou HJ, Young L, Xiao H, Min W. Mitochondrial thioredoxin-2 maintains HCN4 expression and prevents oxidative stress-mediated sick sinus syndrome. J Mol Cell Cardiol. 2020 Jan; 138: 291-303. [PMID: 31751569]; [DOI: 10.1016/j.yjmcc.2019.10.009].

29. Kuß J, Stallmeyer B, Goldstein M, Rinné S, Pees C, Zumhagen S, Seebohm G, Decher N, Pott L, Kienitz MC, Schulze-Bahr E. Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K+ Channel) Channel Function. Circ Genom Precis Med. 2019 Jan; 12(1): e002238. [PMID: 30645171]; [DOI: 10.1161/CIRCGEN.118.002238].

30. Tse G, Liu T, Li KH, Laxton V, Wong AO, Chan YW, Keung W, Chan CW, Li RA. Tachycardia-bradycardia syndrome: Electrophysiological mechanisms and future therapeutic approaches (Review). Int J Mol Med. 2017 Mar; 39(3): 519-526. [PMID: 28204831]; [DOI: 10.3892/ijmm.2017.2877].

31. Mulpuru SK, Madhavan M, McLeod CJ, Cha YM, Friedman PA. Cardiac Pacemakers: Function, Troubleshooting, and Management: Part 1 of a 2-Part Series. J Am Coll Cardiol. 2017 Jan 17; 69(2): 189-210. [PMID: 28081829]; [DOI: 10.1016/j.jacc.2016.10.061]

32. Poole JE1, Gleva MJ, Mela T, Chung MK, Uslan DZ, Borge R, Gottipaty V, Shinn T, Dan D, Feldman LA, Seide H, Winston SA, Gallagher JJ, Langberg JJ, Mitchell K, Holcomb R. Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. Circulation. 2010 Oct 19; 122(16): 1553-61. [PMID: 20921437]; [DOI: 10.1161/CIRCULATIONAHA.110.976076]

33. Nielsen JC1, Thomsen PE, Hojberg S, Møller M, Vesterlund T, Dalsgaard D, Mortensen LS, Nielsen T, Asklund M, Friis EV, Christensen PD, Simonsen EH, Eriksen UH, Jensen GV, Svendsen JH, Toff WD, Healey JS, Andersen HR. A comparison of single-lead atrial pacing with dual-chamber pacing in sick sinus syndrome. Eur Heart J. 2011 Mar; 32(6): 686-96. [PMID: 21300730]; [DOI: 10.1093/eurheartj/ehr022]

34. Senaratne J, Herath TT, Beaudette D, Irwin M, Gulamhusein S, Senaratne MP. Safety and efficacy of AAIR pacing in selected patients with sick sinus syndrome. Medicine (Baltimore) 2018 Oct; 97(42): e12833. [PMID: 30334983]; [DOI: 10.1097/MD.0000000000012833]

35. Boink GJ, Robinson RB. Gene therapy for restoring heart rhythm. J Cardiovasc Pharmacol Ther. 2014 Sep; 19(5): 426-38. [PMID: 24742766]; [DOI: 10.1177/1074248414528575]

36. Chauveau S, Brink PR, Cohen IS. Stem cell-based biological pacemakers from proof of principle to therapy: a review. Cytotherapy. 2014 Jul; 16(7): 873-80. [PMID: 24831844]; [DOI: 10.1016/j.jcyt.2014.02.014]

37. Rosen MR. Gene therapy and biological pacing. N Engl J Med. 2014 Sep 18; 371(12): 1158-9. [PMID: 25229921]; [DOI: 10.1056/NEJMcibr1408897]

38. Saito Y, Nakamura K, Ito H. Cell-based Biological Pacemakers: Progress and Problems. Acta Med Okayama. 2018 Feb; 72(1): 1-7. [PMID: 29463932]; [DOI: 10.18926/AMO/55656]

39. Meyers JD, Jay PY, Rentschler S. Reprogramming the conduction system: Onward toward a biological pacemaker. Trends Cardiovasc Med. 2016 Jan; 26(1): 14-20. [PMID: 25937044]; [DOI: 10.1016/j.tcm.2015.03.015]

40. Anghel TM, Pogwizd SM. Creating a cardiac pacemaker by gene therapy. Med Biol Eng Comput. 2007 Feb; 45(2): 145-55. [PMID: 17139515]; [DOI: 10.1007/s11517-006-0135-0]

41. Keith A, Flack M. The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart Circ Arrhythm Electrophysiol. J Anat Physiol. 1907 Apr; 41(Pt 3): 172-89. [PMID: 17232727]

42. Li N, Hansen BJ, Csepe TA, Zhao J, Ignozzi AJ, Sul LV, Zakharkin SO, Kalyanasundaram A, Davis JP, Biesiadecki BJ, Kilic A, Janssen PML, Mohler PJ Weiss R, Hummel JD, Fedorov VV. Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure. Sci Transl Med. 2017 Jul 26; 9(400). [PMID: 28747516]; [10.1126/scitranslmed.aam5607]

43. Csepe TA, Zhao J, Hansen BJ, Li N, Sul LV, Lim P, Wang Y, Simonetti OP, Kilic A, Mohler PJ, Janssen PM, Fedorov VV. Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways. J Vet Cardiol. 2019 Apr; 22: 2-19. [PMID: 30559056]; [DOI: 10.1016/j.jvc.2018.10.004]

44. Kalyanasundaram A, Li N, Hansen BJ, Zhao J, Fedorov VV. Canine and human sinoatrial node: differences and similarities in the structure, function, molecular profiles, and arrhythmia. [PMID: 30559056]; [DOI: 10.1016/j.jvc.2018.10.004]

45. Liang X, Evans SM, Sun Y. Development of the cardiac pacemaker. Cell Mol Life Sci. 2017 Apr; 74(7): 1247-1259. [PMID: 30235141]; [DOI: 10.1109/TNB.2018.2870331]

46. Choudhury M, Boyett MR, Morris GM. Biology of the Sinus Node and its Disease. Arrhythm Electrophysiol Rev. 2015 May; 4(1): 28-34. [PMID: 26835096]; [DOI: 10.15420/aer.2015.4.1.28]

47. John RM, Kumar S. Sinus Node and Atrial Arrhythmias. Circulation. 2016 May 10; 133(19): 1892-900. [PMID: 27166347]; [DOI: 10.1161/CIRCULATIONAHA.116.018011]

48. Morris GM, Kalman JM. Fibrosis, electrics and genetics. Perspectives in sinoatrial node disease. Circ J. 2014; 78(6): 1272-82. [PMID: 24837708]; [DOI: 10.1253/circj.cj-14-0419]

49. Zhong H, Wang T, Lian G, Xu C, Wang H, Xie L. TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling. Heart Vessels. 2018 Sep; 33(9): 1094-1105. [PMID: 29511803]; [DOI: 10.1007/s00380-018-1146-0]

50. Jansen JA, van Veen TA, de Bakker JM, van Rijen HV. Cardiac connexins and impulse propagation. J Mol Cell Cardiol. 2010 Jan; 48(1): 76-82. [PMID: 19729017]; [DOI: 10.1016/j.yjmcc.2009.08.018]

51. Yassin AS, Subahi A, Abubakar H, Rashed A, Shokr M. Sick Sinus Syndrome and Takotsubo Cardiomyopathy. Case Rep Cardiol. 2018 Aug 19; 2018: 3868091. [PMID: 30210876]; [DOI: 10.1155/2018/3868091]

52. Wiese C, Grieskamp T, Airik R, Mommersteeg MT, Gardiwal A, de Gier-de Vries C, Schuster-Gossler K, Moorman AF, Kispert A, Christoffels VM. Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ Res. 2009 Feb 13; 104(3): 388-97. [PMID: 19096026]; [DOI: 10.1161/CIRCRESAHA.108.187062]

53. Hoogaars WM, Engel A, Brons JF, Verkerk AO, de Lange FJ, Wong LY, Bakker ML, Clout DE, Wakker V, Barnett P, Ravesloot JH, Moorman AF, Verheijck EE, Christoffels VM. Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria. Genes Dev. 2007 May 1; 21(9): 1098-112. [17473172]; [DOI: 10.1101/gad.416007]

54. Hashem SI, Lam ML, Mihardja SS, White SM, Lee RJ, Claycomb WC. Shox2 regulates the pacemaker gene program in embryoid bodies. Stem Cells Dev. 2013 Nov 1; 22(21): 2915-26. [PMID: 23767866]; [DOI: 10.1089/scd.2013.0123]

55. Ye W, Wang J, Song Y, Yu D, Sun C, Liu C, Chen F, Zhang Y, Wang F, Harvey RP, Schrader L, Martin JF, Chen Y. A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaker cell fate in the pulmonary vein myocardium and sinoatrial node. Development. 2015 Jul 15; 142(14): 2521-32. [PMID: 26138475]; [DOI: 10.1242/dev.120220]

56. Liang X, Zhang Q, Cattaneo P, Zhuang S, Gong X, Spann NJ, Jiang C, Cao X, Zhao X, Zhang X, Bu L, Wang G, Chen HS, Zhuang T, Yan J, Geng P, Luo L, Banerjee I, Chen Y, Glass CK, Zambon AC, Chen J, Sun Y, Evans SM. Transcription factor ISL1 is essential for pacemaker development and function. J Clin Invest. 2015 Aug 3; 125(8): 3256-68. [PMID: 26193633]; [DOI: 10.1172/JCI68257]

57. Espinoza-Lewis RA, Yu L, He F, Liu H, Tang R, Shi J, Sun X, Martin JF, Wang D, Yang J, Chen Y. Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5. Dev Biol. 2009 Mar 15; 327(2): 376-85. [PMID: 19166829]; [DOI: 10.1016/j.ydbio.2008.12.028]

58. Wang J, Bai Y, Li N, Ye W, Zhang M, Greene SB, Tao Y, Chen Y, Wehrens XH, Martin JF. Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation. Proc Natl Acad Sci U S A. 2014 Jun 24; 111(25): 9181-6. [PMID: 24927531]; [DOI: 10.1073/pnas.1405411111]

59. van Eif VWW, Devalla HD, Boink GJJ, Christoffels VM. Transcriptional regulation of the cardiac conduction system. Nat Rev Cardiol. 2018 Oct; 15(10): 617-630. [PMID: 29875439]; [DOI: 10.1038/s41569-018-0031-y]

60. Hoffmann S, Berger IM, Glaser A, Bacon C, Li L, Gretz N, Steinbeisser H, Rottbauer W, Just S, Rappold G. Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia. Basic Res Cardiol. 2013 Mar; 108(2): 339. [PMID: 23455426]; [DOI: 10.1007/s00395-013-0339-z]

61. Vedantham V, Galang G, Evangelista M, Deo RC, Srivastava D. RNA sequencing of mouse sinoatrial node reveals an upstream regulatory role for Islet-1 in cardiac pacemaker cells. Circ Res. 2015 Feb 27; 116(5): 797-803. [PMID: 25623957]; [DOI: 10.1161/CIRCRESAHA.116.305913]

62. Baruscotti M, Barbuti A, Bucchi A. The cardiac pacemaker current. J Mol Cell Cardiol. 2010 Jan; 48(1): 55-64. [PMID: 19591835]; [DOI: 10.1016/j.yjmcc.2009.06.019]

63. Ishikawa T, Ohno S, Murakami T, Yoshida K, Mishima H, Fukuoka T, Kimoto H, Sakamoto R, Ohkusa T, Aiba T, Nogami A, Sumitomo N, Shimizu W, Yoshiura KI, Horigome H, Horie M, Makita N. Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction. Heart Rhythm. 2017 May; 14(5): 717-724. [PMID: 28104484]; [DOI: 10.1016/j.hrthm.2017.01.020]

64. Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res. 2000 Sep; 47(4): 658-87. [PMID: 10974216]; [DOI: 10.1016/s0008-6363(00)00135-8]

65. Li N, Csepe TA, Hansen BJ, Dobrzynski H, Higgins RS, Kilic A, Mohler PJ, Janssen PM, Rosen MR, Biesiadecki BJ, Fedorov VV. Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart. Circ Arrhythm Electrophysiol. 2015 Oct; 8(5): 1219-27. [PMID: 26304511]; [DOI: 10.1161/CIRCEP.115.003070]

66. Stieber J, Herrmann S, Feil S, Löster J, Feil R, Biel M, Hofmann F, Ludwig A. The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad Sci U S A. 2003 Dec 9; 100(25): 15235-40. [PMID: 14657344]; [DOI: 10.1073/pnas.2434235100]

67. Baruscotti M, Bucchi A, Viscomi C, Mandelli G, Consalez G, Gnecchi-Rusconi T, Montano N, Casali KR, Micheloni S, Barbuti A, DiFrancesco D. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Natl Acad Sci U S A. 2011 Jan 25; 108(4): 1705-10. [PMID: 21220308]; [DOI: 10.1073/pnas.1010122108]

68. Verkerk AO, Wilders R. Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current. Int J Mol Sci. 2015 Jan 29; 16(2): 3071-94. [PMID: 25642760]; [DOI: 10.3390/ijms16023071]

69. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med. 2006 Jan 12; 354(2): 151-7. 2018 Feb; 28(2): 154-155. [PMID: 16407510]; [DOI: 10.1056/NEJMoa052475]

70. Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, Dascal N, Eldar M, Glikson M. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation. 2007 Jul 31; 116(5): 463-70. [PMID: 17646576]; [DOI: 10.1161/CIRCULATIONAHA.107.706887]

71. Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest. 2003 May; 111(10): 1537-45. [PMID: 12750403]; [DOI: 10.1172/JCI16387]

72. Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004 Jun 25; 279(26): 27194-8. [PMID: 15123648]; [DOI: 10.1074/jbc.M311953200]

73. Netter MF, Zuzarte M, Schlichthörl G, Klöcker N, Decher N. The HCN4 channel mutation D553N associated with bradycardia has a C-linker mediated gating defect. Cell Physiol Biochem. 2012; 30(5): 1227-40. [PMID: 23075627]; [DOI: 10.1159/000343314]

74. Amin AS, Asghari-Roodsari A, Tan HL. Cardiac sodium channelopathies. Pflugers Arch. 2010 Jul; 460(2): 223-37. [PMID: 20091048]; [DOI: 10.1007/s00424-009-0761-0]

75. Savio-Galimberti E, Argenziano M, Antzelevitch C. Cardiac Arrhythmias Related to Sodium Channel Dysfunction. Handb Exp Pharmacol. 2018; 246: 331-354. [PMID: 28965168]; [DOI: 10.1007/164_2017_43]

76. Remme CA. Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects. J Physiol. 2013 Sep 1; 591(17): 4099-116. [PMID: 23818691]; [DOI: 10.1113/jphysiol.2013.256461]

77. Jenewein T, Beckmann BM, Rose S, Osterhues HH, Schmidt U, Wolpert C, Miny P, Marschall C, Alders M, Bezzina CR, Wilde AAM, Kääb S, Kauferstein S. Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene. Forensic Sci Int. 2017 Jun; 275: 187-194. [PMID: 28391114]; [DOI: 10.1016/j.forsciint.2017.02.038]

78. Yeates L, Ingles J, Gray B, Singarayar S, Sy RW Semsarian C, Bagnall RD. A balanced translocation disrupting SCN5A in a family with Brugada syndrome and sudden cardiac death. Heart Rhythm. 2019 Feb; 16(2): 231-238. [PMID: 30170230]; [DOI: 10.1016/j.hrthm.2018.08.027]

79. Zhang J, Wei F, Ding L, Wang L, Zhang X, Yu L, Liu R, Kuang X, Jiao B, Yang B, Fan J. MicroRNA-1976 regulates degeneration of the sinoatrial node by targeting Cav1.2 and Cav1.3 ion channels. J Mol Cell Cardiol. 2019 Sep; 134: 74-85. [PMID: 31302118]; [DOI: 10.1016/j.yjmcc.2019.06.018].

80. Baig SM, Koschak A, Lieb A, Gebhart M, Dafinger C, Nürnberg G, Ali A, Ahmad I, Sinnegger-Brauns MJ, Brandt N, Engel J, Mangoni ME, Farooq M, Khan HU, Nürnberg P, Striessnig J, Bolz HJ. Loss of Ca(v)1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci. 2011 Jan; 14(1): 77-84. [PMID: 21131953]; [DOI: 10.1038/nn.2694].

81. Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3’UTR evolution. Cell. 2005 Dec 16; 123(6): 1133-46. [PMID: 16337999]; [DOI: 10.1016/j.cell.2005.11.023].

82. Luo X, Zhang H, Xiao J, Wang Z. Regulation of human cardiac ion channel genes by microRNAs: theoretical perspective and pathophysiological implications. Cell Physiol Biochem. 2010; 25(6): 571-86. [PMID: 20511702]; [DOI: 10.1159/000315076].

83. van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson JA, Olson EN. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006 Nov 28; 103(48): 18255-60. [PMID: 17108080]; [DOI: 10.1073/pnas.0608791103].

84. Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G, Wang Z. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 2007 Apr; 13(4): 486-91.[PMID: 17401374]; [DOI: 10.1038/nm1569].

85. Cañón S, Caballero R, Herraiz-Martínez A, Pérez-Hernández M, López B, Atienza F, Jalife J, Hove-Madsen L, Delpón E, Bernad A. miR-208b upregulation interferes with calcium handling in HL-1 atrial myocytes: Implications in human chronic atrial fibrillation. J Mol Cell Cardiol. 2016 Oct; 99: 162-173. [PMID: 27545043]; [DOI: 10.1016/j.yjmcc.2016.08.012].

86. Bakker ML, Boink GJ, Boukens BJ, Verkerk AO, van den Boogaard M, den Haan AD, Hoogaars WM, Buermans HP, de Bakker JM, Seppen J, Tan HL, Moorman AF, ‘t Hoen PA, Christoffels VM. T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells. Cardiovasc Res. 2012 Jun 1; 94(3): 439-49. [PMID: 22419669]; [DOI: 10.1093/cvr/cvs120].

87. Kapoor N, Liang W, Marbán E, Cho HC. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol. 2013 Jan; 31(1): 54-62. [PMID: 23242162]; [DOI: 10.1038/nbt.2465].

88. Ionta V, Liang W, Kim EH, Rafie R, Giacomello A, Marbán E, Cho HC. SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. Stem Cell Reports. 2015 Jan 13; 4(1): 129-142. [PMID: 25533636]; [DOI: 10.1016/j.stemcr.2014.11.004].

89. Hu YF, Dawkins JF, Cho HC, Marbán E, Cingolani E. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci Transl Med. 2014 Jul 16; 6(245): 245ra94. [PMID: 25031269]; [DOI: 10.1126/scitranslmed.3008681].

90. Choudhury M, Black N, Alghamdi A, D’Souza A, Wang R, Yanni J, Dobrzynski H, Kingston PA, Zhang H, Boyett MR, Morris GM. TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome. J Physiol. 2018 Dec; 596(24): 6141-6155. [PMID: 30259525]; [DOI: 10.1113/JP276508].

91. Gorabi AM, Hajighasemi S, Khori V, Soleimani M, Rajaei M, Rabbani S, Atashi A, Ghiaseddin A, Saeid AK, Ahmadi Tafti H, Sahebkar A.Functional biological pacemaker generation by T-Box18 protein expression via stem cell and viral delivery approaches in a murine model of complete heart block. Pharmacol Res. 2019 Mar; 141: 443-450. [PMID: 30677516]; [DOI: 10.1016/j.phrs.2019.01.034].

92. Cho HC, Marbán E.Biological therapies for cardiac arrhythmias: can genes and cells replace drugs and devices? Circ Res. 2010 Mar 5; 106(4): 674-85. [PMID: 20203316]; [DOI: 10.1161/CIRCRESAHA.109.212936]

93. Protze SI, Liu J, Nussinovitch U, Ohana L, Backx PH, Gepstein L, Keller GM.Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker. Nat Biotechnol. 2017 Jan; 35(1): 56-68. [PMID: 27941801]; [DOI: 10.1038/nbt.3745].

94. Rosen MR, Robinson RB, Brink PR, Cohen IS. The road to biological pacing. Nat Rev Cardiol 2011; 8(11): 656-666. [PMID: 21844918]; [DOI: 10.1038/nrcardio.2011.120]

95. Qu J, Plotnikov AN, Danilo P Jr, Shlapakova I, Cohen IS, Robinson RB, Rosen MR.Expression and function of a biological pacemaker in canine heart. Circulation. 2003 Mar 4; 107(8): 1106-9. [PMID: 12615786]; [DOI: 10.1161/01.cir.0000059939.97249.2c].

96. Morris GM, D’Souza A, Dobrzynski H, Lei M, Choudhury M, Billeter R, Kryukova Y, Robinson RB, Kingston PA, Boyett MR. Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression. Cardiovasc Res. 2013 Oct 1; 100(1): 160-9. [PMID: 23787003]; [DOI: 10.1093/cvr/cvt164].

97. Potapova I, Plotnikov A, Lu Z, Danilo P Jr, Valiunas V, Qu J, Doronin S, Zuckerman J, Shlapakova IN, Gao J, Pan Z, Herron AJ, Robinson RB, Brink PR, Rosen MR, Cohen IS. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ Res. 2004 Apr 16; 94(7): 952-9. Epub 2004 Feb 26. [PMID: 14988226]; [DOI: 10.1161/01.RES.0000123827.60210.72].

98. Chauveau S, Brink PR, Cohen IS. Stem cell-based biological pacemakers from proof of principle to therapy: a review. Cytotherapy. 2014 Jul; 16(7): 873-80. [PMID: 24831844]; [DOI: 10.1016/j.jcyt.2014.02.014].

99. Kong CW, Akar FG, Li RA.Translational potential of human embryonic and induced pluripotent stem cells for myocardial repair: insights from experimental models. Thromb Haemost. 2010 Jul; 104(1): 30-8. [PMID: 20539906]; [DOI: 10.1160/TH10-03-0189].

100. Weng Z, Kong CW, Ren L, Karakikes I, Geng L, He J, Chow MZ, Mok CF, Chan, Webb, Keung W, Chow H, Miller, Leung AY, Hajjar RJ, Li RA, Chan CW. A simple, cost-effective but highly efficient system for deriving ventricular cardiomyocytes from human pluripotent stem cells. Stem Cells Dev. 2014 Jul 15; 23(14): 1704-16. [PMID: 24564569]; [DOI: 10.1089/scd.2013.0509].

101. Xue T, Cho HC, Akar FG, Tsang SY, Jones SP, Marbán E, Tomaselli GF, Li RA. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation. 2005 Jan 4; 111(1): 11-20. [PMID: 15611367]; [DOI: 10.1161/01.CIR.0000151313.18547.A2]

102. Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, Arbel G, Huber I, Satin J, Itskovitz-Eldor J, Gepstein L.Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol. 2004 Oct; 22(10): 1282-9.[PMID: 15448703]; [DOI: 10.1038/nbt1014].

103. Mummery CL, Zhang J, Ng ES, Elliott DA, Elefanty AG, Kamp TJ. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview.Circ Res. 2012 Jul 20; 111(3): 344-58. [PMID: 22821908]; [DOI: 10.1161/CIRCRESAHA.110.227512].

104. Zhu WZ, Xie Y, Moyes KW, Gold JD, Askari B, Laflamme MA. Neuregulin/ErbB signaling regulates cardiac subtype specification in differentiating human embryonic stem cells. Circ Res. 2010 Sep 17; 107(6): 776-86. [PMID: 20671236]; [DOI: 10.1161/CIRCRESAHA.110.223917].

105. Birket MJ, Ribeiro MC, Verkerk AO, Ward D, Leitoguinho AR, den Hartogh SC, Orlova VV, Devalla HD, Schwach V, Bellin M, Passier R, Mummery CL. Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells. Nat Biotechnol. 2015 Sep; 33(9): 970-9. [PMID: 26192318]; [DOI: 10.1038/nbt.3271].

106. Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ, Kolaja KL, Swanson BJ, January CT. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol. 2011 Nov; 301(5): H2006-17. [PMID: 21890694]; [DOI: 10.1152/ajpheart.00694.2011].

107. Zhao H, Wang F, Tang Y, Wang X, Wang T, Zhao Q, Huang C. HCN2 and TBX3 Reprogram Human-Induced Pluripotent Stem Cells-Derived Cardiomyocytes into Pacemaker-Like Cells. DNA Cell Biol. 2020 Feb; 39(2): 289-298. [PMID: 31916853]; [DOI: 10.1089/dna.2019.5135].

108. Yang L, Zhu S, Li Y, Zhuang J, Chen J, Huang H, Chen Y, Wen Y, Wen Y, Guo H, Fan X, Yuan W, Jiang Z, Wang Y, Wu X, Zhu P. Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells. Curr Mol Med. 2019 Oct 17. [PMID: 31749426]; [DOI: 10.2174/1566524019666191017150416].

109. Ruan Z, Zhu L, Yin Y, Chen G. Overexpressing NKx2.5 increases the differentiation of human umbilical cord drived mesenchymal stem cells into cardiomyocyte-like cells. Biomed Pharmacother. 2016 Mar; 78: 110-115. [PMID: 26898431]; [DOI: 10.1016/j.biopha.2016.01.020].

110. Xu R, Chen W, Zhang Z, Qiu Y, Wang Y, Zhang B, Lu W. Integrated data analysis identifies potential inducers and pathways during the endothelial differentiation of bone-marrow stromal cells by DNA methyltransferase inhibitor, 5-aza-2’-deoxycytidine. Gene. 2018 May 30; 657: 9-18. [PMID: 29514045]; [DOI: 10.1016/j.gene.2018.03.010].

111. Wang DG, Zhang FX, Chen ML, Zhu HJ, Yang B, Cao KJ. Cx43 in mesenchymal stem cells promotes angiogenesis of the infarcted heart independent of gap junctions. Mol Med Rep. 2014 Apr; 9(4): 1095-102. [PMID: 24481773]; [DOI: 10.3892/mmr.2014.1923].

112. Yang XJ, Zhou YF, Li HX, Han LH, Jiang WP. Mesenchymal stem cells as a gene delivery system to create biological pacemaker cells in vitro. J Int Med Res. 2008 Sep-Oct; 36(5): 1049-55. [PMID: 18831900]; [DOI: 10.1177/147323000803600523].


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