Submit Manuscript    >>    Login | Register

Genetics and Sinus Node Dysfunction

Genetics and Sinus Node Dysfunction
Quick View
Credits:Eyal Nof MD1, 2, Michael Glikson MD2  and  Charles Antzelevitch PhD1
From 1Masonic Medical Research Laboratory, Utica NY, 2Heart Institute, Chaim Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Israel

Running Title:Genetics and Sinus Node Dysfunction

Address for correspondence: Charles Antzelevitch, PhD, Gordon K. Moe Scholar, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, New York 13501.


Sinus node dysfunction (SND) is commonly encountered in the clinic.  The clinical phenotype ranges from asymptomatic sinus bradycardia to complete atrial standstill. In some cases, sinus bradycardia is associated with other myocardial conditions such as congenital abnormalities, myocarditis, dystrophies, cardiomyopathies as well as fibrosis or other structural remodeling of the SA node [1-8]. Although there are many etiologies for symptomatic slow heart rates, the only effective treatment available today is the implantation of a pacemaker. The predominant ion channel currents contributing to the pacemaker activity in the sinoatrial node (SAN) include currents flowing through hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels [9], L- type Ca, T- type Ca [10], delayed rectifier K [11,12], and acetylcholine (ACh)-activated [13,14] channels. However, their relative contribution remains a matter of debate and the cellular mechanisms contributing to abnormal sinus node function leading to bradycardia are not fully elucidated.  Sodium channel current (INa), encoded by SCN5A, is responsible for the cardiac action potential (AP) upstroke and therefore has an important role in initiation and propagation of the cardiac action potential. Although it is largely absent in the sinus node, it plays an important role at the periphery of the sinus node in transmitting  electrical activity from the sinus node to the rest of the atria. Mutations in genes encoding structural anchoring proteins (ANK2, Caveolin- 3, AKAP9) have been associated with the development of atrial as well as ventricular arrhythmias [15, 16, 17].  Sinus node dysfunction has been associated with a variety of atrial tachyarrhythmias, atrial fibrillation (AF) in particular. In recent years, numerous publications have focused on the genetic basis for ion channels and structural protein remodeling, providing further insights in the mechanisms of sinus node dysfunction and its role in AF. In this review, we will focus on the genetic aspects of the various forms of sinus node dysfunction and their relation to AF.


Mutations in the gene encoding the HCN4 ion channel have been shown to be associated with inherited sinus bradycardia [18-21].  HCN4 encodes the protein that contributes to formation of If channels, which participate in spontaneous diastolic membrane depolarization of sinoatrial node cells [22 - 25]. Modulation of these channels by cAMP is believed to be responsible for acceleration of heart rate [23] . Four HCN gene family members have been cloned, three of which are present in heart (HCN1, HCN2, HCN4).  HCN4 is the most prominent HCN transcript in the atria, whereas HCN2 is the dominant transcript in the ventricle [9, 26]. SA cells from knock out mice lacking HCN4 have 75% less I and SA cells from mice lacking HCN2 have 25% less HCN current [27 - 30]. Of note in humans, HCN2 and HCN4 were found to be the dominant mRNA transcripts [31].

To date, five HCN4 mutations have been reported in humans.  Two described symptomatic patients with malignant syncope [19, 32].  One of these patients also suffered from bouts of AF [19].  In this case, the patient had a stop codon resulting in the deletion of the cyclic nucleotide binding domain (CNBD), making the mutant channels insensitive to cAMP. In the second case [33], a missense mutation in HCN4, affecting trafficking of the mutant channel, segregated among family members with a prolonged QTc. The proband had an episode of torsade de pointes (TdP). The basis for association of a prolonged QTc with a decrease in HCN4 current amplitude is unclear, since a loss of function of If is not expected to prolong the QT interval, other than through a reduction in heart rate. Studies in both humans [34, 35] and mice [36] have not observed prolongation of the QTc in response to If blockers. 

Two large  families with mutations in HCN4 causing asymptomatic bradycardia have been reported by us and others [18, 21]. A missence mutation (S672R) was found by Milanesi et al [18] to be associated with asymptomatic bradycardia. Despite its location in the CNBD, this mutation did not affect the binding properties of cAMP, but changed the biophysical properties of the channel. Mutant channels deactivated slower and the voltage-dependence of activation shifted in the hyperpolarizing direction, leading to a decrease in If , responsible for the slowing of the heart rate  [18, 37].

We described [21] a family with asymptomatic sinus bradycardia with no extracardiac abnormalities, managed conservatively during long term follow-up (14±11years). All affected family members were asymptomatic with normal exercise capacity during long-term follow-up. Electrophysiological testing performed on 2 affected family members confirmed significant isolated sinus node dysfunction. Genetic analysis revealed a missence mutation (G480R) in the HCN4 channel pore. Our in vitro expression studies suggested that sinus bradycardia in affected family members was likely due to combined synthesis and trafficking defects as well as altered biophysical properties of the mutant HCN4 channels. 

We recently [38] identified 2 families with symptomatic bradycardia. Affected members presented with a history of presyncope, except for one subject who had a poorly documented event of loss of consciousness with apparent cardiopulmonary arrest, which resolved following basic CPR; he recovered without defibrillation. There were no documented events of syncope and all had a normal exercise test.  Sequencing of the HCN4 gene in the probands of these families revealed a new heterozygous A485V missense mutation within the pore-forming region of the channel.  A485 is a conserved residue not found in 50 controls.  We are currently extending the genetic analysis to exclude other genetic variations.

The common feature of these familial bradycardia cases is a relatively benign prognosis and lack of chronotropic incompetence.  These findings are in partial agreement with a study conducted in the adult HCN4 knockout mouse model reported  by Herrmann et al [39]. Like the families described, the knockout mice had no impairment of heart rate response during exercise. However, instead of bradycardia, they displayed sinus pauses.  Taken together, the available animal and human data suggest that while If may be a major contributor to diastolic depolarization at rest, its contribution to the positive chronotropic response of sympathetic stimulation is less clear.

One patient with an HCN4 loss of function mutation had documented AF [19]. It is not clear whether this association is merely a coincidence or whether this genetic defect can predispose to AF. From a theoretical point of view, a loss of function of HCN4 channel current should depress phase 4 of the sinus node action potential as its principal effect and would not be expected to cause any type of atrial arrhythmia. Indeed, over expression of HCN4 in the atria can lead to atrial ectopy leading to initiation of AF.   In a canine heart failure model [40], HCN4 channels were found to be down-regulated in the SN but up regulated in  the right atrium. The authors suggested that atrial HCN4- up regulation may contribute to the increased incidence of atrial arrhythmias in heart failure patients.


Mutations in SCN5A, the gene that encodes the ∝ subunit of the cardiac sodium channel,  have been associated with several rhythm disorders including Brugada syndrome [41], long QT syndrome  type 3 (LQT3) [42] and cardiac conduction disease. Although SCN5A does not play a prominent role in sinus node activity, loss of  function mutations may lead to bradycardia [43 - 49] by reducing excitability and impairing conduction of impulses generated in the sinus node into the atria. Recent studies using Tetrodotoxin (TTX) a selective Na+ current inhibitor have demonstrated that TTX can abolish the action potential upstroke in the periphery of the SA node but not in the center of the SA node [50]. These studies point to the lack of participation of NaV1.5 in the conduction of the electrical impulse through the SA node proper.

Loss of function mutations in SCN5A can lead to a widening of the of the P- wave, prolongation of PR interval as well as widening of the QRS interval in the surface ECG [43 - 49].  Changes in these parameters are often encountered in patients with SCN5A-mediated Brugada syndrome [51] and are due to depression of INa-mediated parameters. In some cases the same mutation has been shown to  lead to both LQT3 and Brugada [52] in the same family or to a combination of progressive cardiac conduction disease and Brugada syndrome [53] or LQT3, Brugada ECG and sinus node dysfunction [44]. This overlap of three syndromes was reported to be the result of a 1795insD SCN5A mutation, which is associated with an increase in late INa , responsible for the LQT3 phenotype, and a negative shift of the voltage-dependence of inactivation, which causes a loss of function of INa responsible for the Brugada and sinus node dysfunction phenotypes [44]. Using a mathematical model of an SA node action potential, the authors argued that the persistent late INa coupled with the negative shift in the voltage-dependence of inactivation caused a prolongation of APD and a slowing of phase 4, which together are responsible for the bradycardia or sinus node dysfunction. Interestingly, the sea anemone toxin, ATX-II, a compound known to increase late Ina,  has been shown to induce a prolonged P-R interval and SA node recovery time as well as LQT3 in intact mouse hearts [50].

In another report [40], compound heterozygous SCN5A mutations were found to be associated with sick sinus syndrome (SSS). Mutation carriers exhibited symptomatic sinus bradycardia progressing to atrial inexcitability, necessitating permanent pacing. Affected carriers also had prolonged HV and QRS intervals. Biophysical characterization of the mutant sodium channels in a heterologous expression system demonstrated loss of function or significant impairments in channel gating (inactivation) that predicted a reduced myocardial excitability.  Here again, sinus bradycardia may be the result of failure of the impulse to conduc into adjacent atrial myocardium [40]. Another possibility may be that INa  has a direct effect on the SN as suggested by Veldkamp et al [44]. 

AF and other supraventricular tachycardias (SVT) have been shown to be associated with an SCN5A mutation (D1275N) segregating among family members with conduction disease [44, 54, 55]. In 2 of these reports, in addition to the above, affected members also presented with a dilated cardiomyopathy. Dilated cardiomyopathy was preceded by AF, SN dysfunction and conduction block [55]. The extent to which SCN5A mutations are related with AF is not clear. It is possible that AF is secondary to structural changes associated with SCN5A mutations, in addition to direct reduction of INa. Interestingly,  Brugada patients are also known to have a relatively high incidence of atrial arrhythmias, AF in particular  [56-60, 61] whether or not the syndrome is caused by SCN5A mutations  [62]. In the SCN5A-related Brugada syndrome cases, as in SCN5A-mediated sinus node dysfunction, AF may be in part related to an abnormal “substrate” in the form of fibrosis as well as the “electrical” impairment. 

Recent studies have reported major difference in the characteristics of the sodium channel between atrial and ventricular cells in the canine heart [63, 64].   These studies showed that steady-state inactivation of the sodium channels was 9 to 16 mV more negative in atrial vs. ventricular myocytes.  This distinction coupled with the more positive resting membrane potential of atrial cells, suggests that a large fraction of sodium channels are inactivated and unavailable at the normal resting membrane potential of atrial cells. Consequently, the impact of some SCN5A mutations may be much greater in atria than in ventricles, predisposing to the development of arrhythmias more readily in the atria vs. ventricles [61].


Connexins are gap junction proteins responsible for electrical communication between cells. Connexin (Cx) 40 (encoded by GJA5) is specific to the atria, whereas Cx43 (GJA1) and Cx45 (GJA7) are also expressed in the ventricle [65].  Cx40 defects were found to be associated with AF [66] and atrial standstill (AS) [41]. In a study [66] involving patients with idiopathic AF, 4 out of 15 patients were found to have mutations in GJA5. Interestingly, 3 of them had tissue specific mutations and in only one was the mutation also present in lymphocytes, indicating that the first two are somatic mutations. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling. This gives rise to regions of heterogeneous conduction, providing a substrate for atrial arrhythmias. Of note, none of these patients had a prolonged P wave during sinus rhythm. There are no data on the PR interval in these patients. All of them had a normal QRS interval, which is consistent with the fact that Cx40 is not present in the ventricle.  In 2003, a large family with progressive atrial standstill was reported [41]. Symptoms started in the late twenties to thirties and progressed to total AS necessitating implantation of a pacemaker. Genetic analysis revealed that affected individuals in the family inherited both the D1275N missense mutation in SCN5A. In addition, two closely linked polymorphisms were identified in the regulatory regions of the gene for connexin40 (Cx40) leading to a loss of function. The D1275N SCN5A mutant channels shifted the activation curve to more positive voltages, predicting a loss of function of INa and consequently reduced excitability. It is noteworthy that family members with D1275N alone or the rare Cx40 genotype alone were not clinically affected. Thus, familial AS in this case was associated with the occurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene. Although the functional effect of each genetic change is relatively benign, the combined effect of the genetic variants led to the development of AS.  Prior to AS, 2 of the 4 affected family members had atrial arrhythmias. Thus, at present evidence exists that mutations in Cx40 can cause AF, but there is no evidence indicating that Cx40 mutations alone can result in AS.


KCNQ1 encodes the ∝ subunit of the voltage- gated slowly activating delayed rectifier K+ channel responsible for IKs. Mutations in this gene have been linked to LQT1 (loss of function) [67, 68] , Short QT (SQT) 2 (gain of function) [69] and AF (gain of function) [70]. In 2005, Hong et al. reported a case in which a de novo mutation in KCNQ1 (V141M) was responsible for AF and SQT [71]. Interestingly, the child carrying this mutation was born with severe bradycardia. In a computerized model, this mutation caused a shortening of APD. The abbreviated APD in the ventricle explains the SQT phenotype while the abbreviated APD in the atrium can explain the AF phenotype. In addition, the enhanced outward IKs in sinoatrial cells, could lead to a shift of resting membrane voltage to more negative potentials. The authors speculated that this might slow or halt spontaneous firing of the SN cells in vivo causing AS. Of note, this is the only KCNQ1 mutation reported to affect SN cell activity. The absence of P waves associated with irregular heart rate in this child theoretically may actually be due to AF and not to AS. Accordingly, the slow ventricular response may be due to a diseased AV conduction rather than slowed SN activity.


Protein encoded by the ANK2 gene is a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying cytoskeleton.  Ankyrins play a role in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Ankyrin- B (ANKB or ANK2) is a membrane adaptor protein. Mutations in this gene have been identified as the cause of LQT4 [15, 72, 73]. Mutations in this gene increase the total intracellular calcium by reducing the expression of Na/ K ATPase and Na/ Ca exchanger in the face of unchanged Ca 2+ entry by ICa. This increase is most probably responsible for the early after depolarization (EAD) and delayed after depolarization (DAD) seen in knockout AnkB+/- mice leading to polymorphic ventricular tachycardia [15]. LQT4 has several distinctive characteristics compared to other LQT syndromes. AnkB is located in both atria and ventricular cells [72], therefore it is not surprising that patients carrying mutations in this gene exhibit a variety of symptoms, including sinus bradycardia, sinus arrhythmia, catecholaminergic ventricular tachycardia, SCD and AF.

In the first large family described, 12 out of 25 affected family members had AF [15]. In this family, all of the affected members as well as all of the knockout AnkB +/- mice displayed sinus bradycardia.   Interestingly, QTc prolongation is not as severe as in other LQT syndromes [15]  and in some the QTc interval is within normal range [72]. Recently, two families with sinus node dysfunction and AF have been associated with mutation in ANKB [74]. Heart rate was lower than 50 bpm in all affected adult individuals. In one family, the rhythm originated in the SN in 7/ 25 affected family members, from the coronary sinus in 7/ 25 and as junctional escape in 11/ 25. Thirteen of them had AF. In the second family, the rhythm originated from the SN in 10/ 13 and from the coronary sinus in 3/ 13 members. Three of them had AF. The prevalence of AF in both families increased with age. The precise mechanism underlying ANKB mutation-mediated sinus bradycardia and AF is not known. One possibility is that the EADs and/or DADs observed in the ventricles of knockout AnkB +/- mice may also develop in the atria. EAD and DAD have been shown to initiate AF in animal models [75-77].  Another possibility may be that both AF and SN dysfunction are a consequence of conduction delay providing the substrate for micro-reentry.

If one takes in account the different interactions ANKB can have with a wide variety of ion channel proteins and transporters, the potential for modulating cardiac function and dysfunction is great and may explain the widely varied phenotypes seen in patients carrying ANKB mutations.


EMD encodes the nuclear membrane protein emerin. Mutations in this gene and lamin A can lead to Emery-Dreifuss muscular dystrophy (EDMD). These nuclear proteins are thought to take part in maintenance of the nuclear envelope structure and in regulation of gene expression [78, 79]. EDMD is characterized by early contractions of elbows, neck extensors and Achilles tendons, rigid spine, slowly progressive humero- peroneal muscle wasting and weakness, and cardiomyopathy with AV conduction block [78, 79]. AF has been associated with EMD in a large family with EDMD [78, 79]. In this family, a mutation (Lys27del) in EMD was sufficient to produce the cardiac phenotype that involved conduction abnormalities in all affected individuals and AF in most. Those exhibiting the full EDMD phenotype had an additional mutation in lamin A.    Recently a Lys27del in EMD was associated with SN dysfunction and AF [80]. Four males presented with SSS and subsequently developed AF. All of them had symptoms of bradycardia, including syncope, in their teenage years. Four asymptomatic females were found to have only non-sustained supraventricular tachycardia events and sinus bradycardia. While all males received a permanent pacemaker at their fourth to eighth decade of life, none of the affected female members needed pacing.  This discrepancy between males and females is explained by the fact the EDMD is an X-linked recessive trait.  Interestingly, although in affected males there was a near total lack of emerin staining in buccal epithelial cells, none of them developed contractures or muscle weakness. Thus, Lys27del- EMD has for an unknown reason a cardio-selective effect. Emerin is involved not only in maintaining nuclear membrane integrity [81] but it was also found to be associate with the intercalated disk in cardiac muscle [82].  This structural role may provide the substrate for AF and conduction disease [83].   


Genetic defects in ion channels as well as structural proteins have been shown to contribute to sinus node dysfunction. In most cases, there is also a clear association with clinical AF. Even in cases in which one-mutation produces both clinical conditions, the mechanisms responsible may not always be the same. In most of the cases discussed, the clinical presentation of SN dysfunction and AF do not appear concurrently.  One typically precedes the other by several years, pointing to multiple pathways by which a genetic mutation may affect the electrical system of the heart. Although, SN dysfunction and AF are both very common clinical conditions, the precise mechanism responsible for each remains a matter of some debate.  Recent molecular genetic findings have provided new insights into the pathophysiological basis for atrial arrhythmias and SN function and dysfunction that hopefully will guide us to improved diagnosis and approaches to therapy.


  1. Albin G, Hayes DL, Holmes DR, Jr. Sinus node dysfunction in pediatric and young adult patients: treatment by implantation of a permanent pacemaker in 39 cases. Mayo Clin Proc. 1985;60:667-672.
  2. Yabek SM, Jarmakani JM. Sinus node dysfunction in children, adolescents, and young adults. Pediatrics. 1978;61:593-598.
  3. Beder SD, Gillette PC, Garson A, Jr., Porter CB, McNamara DG. Symptomatic sick sinus syndrome in children and adolescents as the only manifestation of cardiac abnormality or associated with unoperated congenital heart disease. Am J Cardiol. 1983;51:1133-1136. CrossRef  PubMed
  4. Onat A. Familial sinus node disease and degenerative myopia--a new hereditary syndrome? Hum Genet. 1986;72:182-184. CrossRef  PubMed
  5. von zur MF, Klass C, Kreuzer H, Mall G, Giese A, Reimers CD. Cardiac involvement in proximal myotonic myopathy. Heart. 1998;79:619-621.
  6. Gulotta SJ, Gupta RD, Padmanabhan VT, Morrison J. Familial occurrence of sinus bradycardia, short PR interval, intraventricular conduction defects, recurrent supraventricular tachycardia, and cardiomegaly. Am Heart J. 1977;93:19-29. CrossRef  PubMed
  7. Schneider MD, Roller DH, Morganroth J, Josephson ME. The syndromes of familial atrioventricular block with sinus bradycardia: prognostic indices, electrophysiologic and histopathologic correlates. Eur J Cardiol. 1978;7:337-351.
  8. Isobe M, Oka T, Takenaka H, Imamura H, Kinoshita O, Kasanuki H, Sekiguchi M. Familial sick sinus syndrome with atrioventricular conduction disturbance. Jpn Circ J. 1998;62:788-790. CrossRef  PubMed
  9. Shi W, Wymore R, Yu H, Wu J, Wymore RT, Pan Z, Robinson RB, Dixon JE, McKinnon D, Cohen IS. Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res. 1999;85:e1-e6.
  10. Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol. 1988;395:233-253.
  11. Brahmajothi MV, Morales MJ, Reimer KA, Strauss HC. Regional localization of ERG, the channel protein responsible for the rapid component of the delayed rectifier, K+ current in the ferret heart. Circ Res. 1997;81:128-135.
  12. Brahmajothi MV, Morales MJ, Liu R, Rasmusson RL, Campbell DL, Strauss HC. In situ hybridization reveals extensive diversity of K+ channel mRNA in isolated ferret cardiac myocytes. Circ Res. 1996;78:1083-1089.
  13. Dobrzynski H, Marples DD, Musa H, Yamanushi TT, Henderson Z, Takagishi Y, Honjo H, Kodama I, Boyett MR. Distribution of the muscarinic K+ channel proteins Kir3.1 and Kir3.4 in the ventricle, atrium, and sinoatrial node of heart. J Histochem Cytochem. 2001;49:1221-1234.
  14. Wickman K, Nemec J, Gendler SJ, Clapham DE. Abnormal heart rate regulation in GIRK4 knockout mice. Neuron. 1998;20:103-114. CrossRef  PubMed
  15. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogne K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421:634-639. CrossRef  PubMed
  16. Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114:2104-2112. CrossRef  PubMed
  17. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A. 2007;104:20990-20995. CrossRef
  18. 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;354:151-157. CrossRef  PubMed
  19. 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;111:1537-1545.
  20. 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;1-26.
  21. 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;116:463-470. CrossRef  PubMed
  22. Stieber J, Herrmann S, Feil S, Loster 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;100:15235-15240. CrossRef
  23. DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature. 1991;351:145-147. CrossRef  PubMed
  24. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455-472. CrossRef  PubMed
  25. Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacol Ther. 2005;107:59-79. CrossRef
  26. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem. 2001;268:1646-1652. CrossRef  PubMed
  27. Ludwig A, Budde T, Stieber J, Moosmang S, Wahl C, Holthoff K, Langebartels A, Wotjak C, Munsch T, Zong X, Feil S, Feil R, Lancel M, Chien KR, Konnerth A, Pape HC, Biel M, Hofmann F. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J. 2003;22:216-224. CrossRef  PubMed
  28. Whitaker GM, Angoli D, Nazzari H, Shigemoto R, Accili EA. HCN2 and HCN4 isoforms self-assemble and co-assemble with equal preference to form functional pacemaker channels. J Biol Chem. 2007;282:22900-22909. CrossRef  PubMed
  29. Michels G, Er F, Khan I, Sudkamp M, Herzig S, Hoppe UC. Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation. 2005;111:399-404. CrossRef  PubMed
  30. Er F, Larbig R, Ludwig A, Biel M, Hofmann F, Beuckelmann DJ, Hoppe UC. Dominant-negative suppression of HCN channels markedly reduces the native pacemaker current I(f) and undermines spontaneous beating of neonatal cardiomyocytes. Circulation. 2003;107:485-489. CrossRef  PubMed
  31. Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M. Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J. 1999;18:2323-2329. CrossRef  PubMed
  32. 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;1-26.
  33. 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;1-26.
  34. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58:32-45. CrossRef  PubMed
  35. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536. CrossRef  PubMed
  36. Stieber J, Wieland K, Stockl G, Ludwig A, Hofmann F. Bradycardic and proarrhythmic properties of sinus node inhibitors. Mol Pharmacol. 2006;69:1328-1337. CrossRef  PubMed
  37. 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;1-26.
  38. Laish-Farkash A, Marek D, Brass D, Pras E, Dascal N, Arad M, Nof E, Eldar M, Reznik-Wolf H, Gurevitz O, Glikson M, Luria D. A Novel Mutation in the HCN4 Gene Causes Familial Sinus Bradycardia in Two Unrelated Moroccan Families. Heart Rhythm. 2008;5S:S275 Abstract.
  39. Herrmann S, Stieber J, Stockl G, Hofmann F, Ludwig A. HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice. EMBO J. 2007;26:4423-4432. CrossRef  PubMed
  40. Zicha S, Fernandez-Velasco M, Lonardo G, L'Heureux N, Nattel S. Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc Res. 2005;66:472-481. CrossRef  PubMed
  41. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O'Brien RE, Schultze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature. 1998;392:293-296. CrossRef  PubMed
  42. Bennett PB, Yazawa K, Makita N, George AL, Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376:683-685. CrossRef  PubMed
  43. Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999;23:20-21. CrossRef  PubMed
  44. Veldkamp MW, Wilders R, Baartscheer A, Zegers JG, Bezzina CR, Wilde AA. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families. Circ Res. 2003;92:976-983. CrossRef  PubMed
  45. 45. 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;112:1019-1028.
  46. Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, Van Langen IM, Sandkuijl L, Smits JP, Hulsbeek M, Rook MB, Jongsma HJ, Wilde AA. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res. 2003;92:14-22. CrossRef  PubMed
  47. Herfst LJ, Potet F, Bezzina CR, Groenewegen WA, Le MH, Hoorntje TM, Demolombe S, Baro I, Escande D, Jongsma HJ, Wilde AA, Rook MB. Na+ channel mutation leading to loss of function and non-progressive cardiac conduction defects. J Mol Cell Cardiol. 2003;35:549-557. CrossRef  PubMed
  48. Bezzina CR, Rook MB, Groenewegen WA, Herfst LJ, van der Wal AC, Lam J, Jongsma HJ, Wilde AA, Mannens MM. Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res. 2003;92:159-168. CrossRef  PubMed
  49. Laitinen-Forsblom PJ, Makynen P, Makynen H, Yli-Mayry S, Virtanen V, Kontula K, alto-Setala K. SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias. J Cardiovasc Electrophysiol. 2006;17:480-485. CrossRef  PubMed
  50. Lei M, Huang CL, Zhang Y. Genetic Na+ channelopathies and sinus node dysfunction. Prog Biophys Mol Biol. In press 2008. CrossRef  PubMed
  51. Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W, Breithardt G, Escande D, Schulze-Bahr E, LeMarec H, Wilde AA. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol. 2002;40:350-356. CrossRef  PubMed
  52. Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, Van Langen IM, Tan-Sindhunata G, Bink-Boelkens MT, Der Hout AH, Mannens MM, Wilde AA. A single Na+ channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999;85:1206-1213.
  53. Kyndt F, Probst V, Potet F, Demolombe S, Chevallier JC, Baro I, Moisan JP, Boisseau P, Schott JJ, Escande D, Le Marec H. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation. 2001;104:3081-3086. CrossRef  PubMed
  54. McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia 1. Circulation. 2004;110:2163-2167. CrossRef  PubMed
  55. Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005;293:447-454. CrossRef  PubMed
  56. Eckardt L, Kirchhof P, Loh P, Schulze-Bahr E, Johna R, Wichter T, Breithardt G, Haverkamp W, Borggrefe M. Brugada syndrome and supraventricular tachyarrhythmias: a novel association? J Cardiovasc Electrophysiol. 2001;12:680-685. CrossRef  PubMed
  57. Morita H, Kusano-Fukushima K, Nagase S, Fujimoto Y, Hisamatsu K, Fujio H, Haraoka K, Kobayashi M, Morita ST, Nakamura K, Emori T, Matsubara H, Hina K, Kita T, Fukatani M, Ohe T. Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol. 2002;40:1437-1444. CrossRef  PubMed
  58. Bordachar P, Reuter S, Garrigue S, Cai X, Hocini M, Jais P, Haissaguerre M, Clementy J. Incidence, clinical implications and prognosis of atrial arrhythmias in Brugada syndrome. Eur Heart J. 2004;25:879-884. CrossRef  PubMed
  59. Sacher F, Probst V, Iesaka Y, Jacon P, Laborderie J, Mizon-Gerard F, Mabo P, Reuter S, Lamaison D, Takahashi Y, O'Neill MD, Garrigue S, Pierre B, Jais P, Pasquie JL, Hocini M, Salvador-Mazenq M, Nogami A, Amiel A, Defaye P, Bordachar P, Boveda S, Maury P, Klug D, Babuty D, Haissaguerre M, Mansourati J, Clementy J, Le MH. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study. Circulation. 2006;114:2317-2324. CrossRef  PubMed
  60. Babai Bigi MA, Aslani A, Shahrzad S. Clinical predictors of atrial fibrillation in Brugada syndrome. Europace. 2007;1:947-950. CrossRef  PubMed
  61. Francis J, Antzelevitch C. Atrial fibrillation and Brugada syndrome. J Am Coll Cardiol. 2008;51:1149-1153. CrossRef  PubMed
  62. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada Syndrome. Report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111:659-670. CrossRef  PubMed
  63. Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C. Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation. 2007;116:1449-1457. CrossRef  PubMed
  64. Li GR, Lau CP, Shrier A. Heterogeneity of sodium current in atrial vs epicardial ventricular myocytes of adult guinea pig hearts. J Mol Cell Cardiol. 2002;34:1185-1194. CrossRef  PubMed
  65. Vozzi C, Dupont E, Coppen SR, Yeh HI, Severs NJ. Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol. 1999;31:991-1003. CrossRef  PubMed
  66. Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;354:2677-2688. CrossRef  PubMed
  67. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001;104:569-580. CrossRef  PubMed
  68. Maruoka ND, Steele DF, Au BP, Dan P, Zhang X, Moore ED, Fedida D. alpha-actinin-2 couples to cardiac Kv1.5 channels, regulating current density and channel localization in HEK cells. FEBS Lett. 2000;473:188-194. CrossRef  PubMed
  69. Bellocq C, Van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AA. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109:2394-2397. CrossRef  PubMed
  70. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299:251-254. CrossRef  PubMed
  71. Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, Oliva A, Burashnikov E, Santos-de-Soto J, Grueso-Montero J, Diaz-Enfante E, Brugada P, Sachse F, Sanguinetti MC, Brugada R. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res. 2005;68:433-440. CrossRef  PubMed
  72. Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K, Priori SG, Keating MT, Bennett V. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004;9137-9142. CrossRef
  73. Mohler PJ, Le SS, Denjoy I, Lowe JS, Guicheney P, Caron L, Driskell IM, Schott JJ, Norris K, Leenhardt A, Kim RB, Escande D, Roden DM. Defining the Cellular Phenotype of "Ankyrin-B Syndrome" Variants: Human ANK2 Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes. Circulation. 2007;115:432-441. CrossRef  PubMed
  74. Claude H.Vieyres, Solena Le Scouarnec., Vincet Probst, Herve Le Marec, Peter J.Mohler, Jean- Jacques Schott. Major Sinus Node Dysfunction is the Prevailing Phenotype in Two Large Families Linked to ANK2 Gene. Heart Rhythm. 2008;5S:S72-S73 Abstract.
  75. Burashnikov A, Antzelevitch C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity. Circulation. 2003;107:2355-2360. CrossRef  PubMed
  76. Zhou S, Chang CM, Wu TJ, Miyauchi Y, Okuyama Y, Park AM, Hamabe A, Omichi C, Hayashi H, Brodsky LA, Mandel WJ, Ting CT, Fishbein MC, Karagueuzian HS, Chen PS. Nonreentrant focal activations in pulmonary veins in canine model of sustained atrial fibrillation. Am J Physiol Heart Circ Physiol. 2002;283:H1244-H1252.
  77. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-666. CrossRef  PubMed
  78. Emery AE. Emery-Dreifuss muscular dystrophy - a 40 year retrospective. Neuromuscul Disord. 2000;10:228-232. CrossRef  PubMed
  79. Ben YR, Toutain A, Arimura T, Demay L, Massart C, Peccate C, Muchir A, Llense S, Deburgrave N, Leturcq F, Litim KE, Rahmoun-Chiali N, Richard P, Babuty D, Recan-Budiartha D, Bonne G. Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism? Neurology. 2007;68:1883-1894. CrossRef  PubMed
  80. Karst ML, Herron KJ, Olson TM. X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation. J Cardiovasc Electrophysiol. 2008;19:510-515. CrossRef  PubMed
  81. Yorifuji H, Tadano Y, Tsuchiya Y, Ogawa M, Goto K, Umetani A, Asaka Y, Arahata K. Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane. Neurogenetics. 1997;1:135-140. CrossRef  PubMed
  82. Cartegni L, di Barletta MR, Barresi R, Squarzoni S, Sabatelli P, Maraldi N, Mora M, Di BC, Cornelio F, Merlini L, Villa A, Cobianchi F, Toniolo D. Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy. Hum Mol Genet. 1997;6:2257-2264. CrossRef  PubMed
  83. Mohler PJ, Anderson ME. New insights into genetic causes of sinus node disease and atrial fibrillation. J Cardiovasc Electrophysiol. 2008;19:516-518. CrossRef  PubMed

Biosense Webster
event date
Introduction to AFib
Ablation Specialist

View Ablation Specialists