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Archives of Medical Research
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(2014)
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ORIGINAL ARTICLE
Relationship Between Two Arrhythmias: Sinus Node Dysfunction and Atrial Fibrillation Q1
Jun Zhao, Tong Liu, and Guangping Li Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China Received for publication February 12, 2014; accepted April 21, 2014 (ARCMED-D-14-00089).
We reviewed recent advancements in the relationship between sinus node dysfunction (SND) and atrial fibrillation (AF) and propose some underlying mechanisms in regard to ion and molecular aspects. The amount of clinical and animal experiments have proven the structural and electrophysiological remodeling of sinoatrial node (SAN) and atrium may be related significantly between SND and AF. Atrial remodeling was often related to RAS activation. RAS inhibitors and statin, which resist in atrial fibrosis, may be novel strategies to prevent or treat both SND and AF. Besides, funny current (If) and Ca2þ clock mainly contributing to the SAN automaticity may be another link between SND and AF. Gap junctions such as Cx40, Cx43 and Cx45 were proven to participate in both automaticity and conductivity of electrical impulses in SAN and atrial tissue, which was accepted as another link between SND and AF. Common genetic mutations such as the emerin gene, SCN5A gene and HCN4 gene mutation were also the mechanism for the correlation between SND and AF. Ó 2014 IMSS. Published by Elsevier Inc. Key Words: Sinus node dysfunction, Atrial fibrillation, Remodeling.
Both sinus node dysfunction (SND) and atrial fibrillation (AF) are ‘‘hard nuts to crack’’ in clinical practice. Remarkably, the incidence of AF was up to 53% in a previous study including 100 patients with SND (1). Recently, two consecutive studies have indicated that there may be a possible link between these two common arrhythmias. We review recent advancement in the relationship between SND and AF and propose some underlying mechanisms in regard to ion and molecular aspects. Recent studies have supported that the structural and electrophysiological changes of sinoatrial node (SAN) and atrium may be related significantly between SND and AF. First, the structural and electrophysiological remodeling related to AF may be an important substrate of SND. Elvan et al. (2) were the first to confirm that the corrected sinus node recovery time (CSNRT) was prolonged along with the decreasing of the maximal and intrinsic heart rates in the pacing-induced AF canine model, which was related to the occurrence of SAN Address reprint requests to: Guangping Li, MD, PhD, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People’s Republic of China; Phone: þ86-22-88328368; FAX: þ86-22-28261158; E-mail: gp_limail@ yahoo.com.cn
remodeling. In other words, AF increased the susceptibility to SND. A recent observation from Chang et al. (3) seemed to provide further evidence to support the specific electrophysiological changes related to SND in 34 patients with AF. They found that local atrial voltage change near the SAN region was associated with a prolonged sinus node recovery time, a longer right atrial activation time, a decreased voltage of the SAN area, and a slower conduction velocity along the crista terminalis (3). Also, the SAN structure itself may be recognized as a substrate for the macro-reentry participated by neurohormonal activation, which has been regarded as an important basis of maintaining AF. Fedorov et al. (4) demonstrated acetylcholine (Ach) and isoproterenol (Iso) were shown to facilitate the pacing-induced AF/AFL by shortening the SAN and atrial repolarization period. ACh/ Iso was also confirmed to regulate the filtering properties of the sinoatrial conduction pathways by regulating the degree of the entrance block. It reminded us that some electrophysiological changes of SAN in SND may increase the inducibility of AF. Recently, we investigated the inducibility of AF in a canine model of SND. Compared with baseline, the atrial effective refractory periods (ERPs) were shortened following the establishment of the canine SND model. After rapid atrial pacing, atrial ERPs were further decreased
0188-4409/$ - see front matter. Copyright Ó 2014 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2014.04.005 ARCMED1915_proof ■ 10-5-2014 17-11-28
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remarkably, and the dispersion of atrial ERPs measured at different pacing cycle lengths (PCLs) showed significant variations. The average duration and inducibility of AF after SND was increased. It seemed that the decreased automaticity and conductivity of sinus node was associated with the shortening of atrial refractoriness, which may increase the inducibility and duration of AF (5). Obviously, there have been some animal experiments to investigate the link between SND and AF. Recently, several clinical investigations tried to reveal that electro-anatomical remodeling of the atria associates with SND and AF. Park et al. (6) included 117 patients with long-standing persistent AF (L-PeAF) who underwent radiofrequency catheter ablation (RFCA). Post-shock sinus node recovery time was proven to be an independent predictor of clinical recurrence of AF after RFCA. The recent study of Chung et al. (7) consecutively enrolled 319 nonvalvular AF patients with SND and without SND who had undergone RFCA for drug refractory AF to investigate the relationship between the type of SND and AF recurrence after RFCA. They confirmed that AF patients with SND without tachycardia-bradycardia (TB) syndrome suffered significantly more bradycardia compared to both AF patients with SND and with TB or those without SND, which was correlated with severe structural and electrical remodeling of the atria. These results suggest that the type of SND might predict the degree of atrial remodeling and predict the outcome after RFCA of AF (7). In contrast, De Sisti et al. (8) found that the right atrial effective refractory period was not changed significantly in the enrolled patients with SND (8). However, the AERP measurements were performed only at a single site and the control group was not age-matched in their study. As mentioned above, numerous studies are apt to admit the association between SND and AF, no matter which one promotes the other clinically and experimentally. However, the potential mechanism between these two common arrhythmias is not fully understood. Recent remarkable progress in molecular biology gives us some novel understandings. The structural remodeling of atrium and SAN in both SND and AF is mainly referred to as fibrosis (9,10), which may be promoted by the renin-angiotensin system (RAS) activation. There is novel evidence to indicate angiotensin II (Ang II) as another participator in the occurrence of AF and SND, respectively. Ang II was confirmed to upregulate connective tissue growth factor (CTGF) and TGF-b gene expression, which proposed SAN and atrial fibrosis as the important substrate of maintaining AF in a canine model of AF (11). In a recent clinical study, 80 patients scheduled for mitral valve replacement surgery were enrolled, whose tissue samples of the left atrial appendages were obtained to detect the degree of fibrosis. It was shown that local expression of Ang II was increased in AF patients, which was correlated with the duration of AF and the expression of collagen type I. mRNA expressions of the angiotensin type 1 receptor (AT1R) and angiotensin-converting enzyme
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(2014)
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(ACE) genes were observed to be markedly upregulated in AF patients (12). It suggested that the blockers of RAS including the antagonists of AT1R and ACE may be effective drugs to treat AF and prevent atrial fibrosis induced by AF. CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) trials has provided the evidence. It was shown that adding candesartan to conventional congestive heart failure (CHF) therapy in 6379 patients with symptomatic CHF and without a history of AF at enrollment led to a lower incidence of new-onset AF (13). Later, Belluzzi et al. (14) proved that ACE inhibitor was also effective in preventing relapses of lone atrial fibrillation in the absence of hypertension and/or heart disease. Meanwhile, another study attempted to reveal the association of SND with RAS. It was shown that in wild-type mice, Ang II infusion activated NADPH oxidase, leading to increased oxidized calmodulin kinase II (ox-CaMKII), SAN cell oxidative stress, apoptosis, even SND (15). In addition, statin was also recently accepted as a novel strategy to prevent AF. Several retrospective studies (16,17) and meta-analysis of RCTs (18) have reported that statin therapy was associated with a lower incidence of postoperative AF and shorter hospital stay. The study of Marin et al. (19) seemed to reveal the potential mechanism of the antifibrillatory effect of statins. As was reported, statin was associated with increased tissue inhibitor of matrix metalloproteinase-1, which was mainly responsible for degrading collagen type I and III (19). Although there is currently a lack of direct clinical evidence that angiotensin receptor blockers and statins can effectively prevent SND, it is believed that the inhibition of atrial fibrosis is effective to prevent or treat both SND and AF. According to a recent study, both RAS inhibitors and statins could prevent and inhibit atrial fibrosis via regulating platelet-derived growth factor/Rac1/nuclear factor-kappa B axis (20). Thus, inhibitors of RAS and statin may be novel strategies to prevent or treat both SND and AF. Until now, expression of over 120 ion channels and associated proteins within the human sinus node and right atrium has been comprehensively characterized (21). Among them, the funny current (If) and Ca2þ clock mainly contributing to the SAN automaticity have recently been paid more attention. Hyperpolarization-activated inward current If is the mixture consisting of Kþ and Naþ channels modulated by intracellular cyclic nucleotide. If encoded mainly by the HCN2 and HCN4 genes is normally responsible for electrical automaticity in sinus node. Impaired If was confirmed to participate in the occurrence of SND and result in both brady- and tachyarrhythmias (22,23). Furthermore, Yeh et al. (24) provide further evidence in a canine model of AF. It was shown that rapid pacing downregulated SAN HCN2/4 and minK subunit expression to reduce currents If and Iks by 48% in SAN. If played much more significant role than Iks in the prolongation of SAN recovery time. Also, no changes are shown in voltage dependence or kinetics IKr, IcaL, and IcaT (24).
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Two Arrhythmias: Sinus Node Dysfunction and Atrial Fibrillation
The Ca2þ clock, triggered by rhythmic spontaneous sarcoplasmic reticulum (SR) Ca2þ release activates Naþ/ Ca2þ exchanger current (INCx) and causes diastolic depolarization as a complementary mechanism of SAN automaticity (25). Thus, it may serve as another possible link between SND and AF. Joung et al. (26) provided direct evidence that Ca2þ clock malfunction at the superior SAN may contribute partially to the SND in a canine model of pacing-induced AF. In detail, they found that isoproterenol-induced late diastolic Cai elevation (LDCAE) was significantly impaired in the superior SAN of dogs with AF, which was associated with obviously reduced type 2 ryanodine receptor (RyR2) expression in the superior SAN. It was only the inability to develop LDCAE in the superior SAN of the dogs with AF that caused the obstacle in acceleration of heart rate (26). Gap junctions may be another possible link between SND and AF, which participate in both automaticity and conductivity of electrical impulses in SAN and atrial tissue. In SAN and atrial tissue, three main connexin (Cx) isoforms have been found: Cx40, Cx43, Cx45. In Cx43 and Cx45 knock-out mice, there is no significant decrease in heart rate, whereas the deletion of Cx40 gene caused the breakthrough activation of pacemaker activity at other locations distant from the SAN (27). However, another recent observation showed that the loss of Cx43 expression decreased the electrical connection in SAN, which may result in SND (28,29). Meanwhile, mutations of genes
coding for connexins in atrial tissue have been considered as a potential substrate in idiopathic AF. A recent study from Igarashi et al. (30) demonstrated that both transgenes of Cx43 and Cx40 improved atrial conduction and prevented AF in Yorkshire swine models (30). However, recent studies did not provide the direct evidence of connexin as another contactor of SND and AF. Further studies are warranted in the near future. In addition, studies on genetics seem to provide additional surprises. In 2008, Karst et al. (31) confirmed that the mutation of the emerin gene encoding the nuclear membrane protein emerin can cause nonsyndromic, X-linked SND and AF in the multigenerational family of malerestricted and asymptomatic SND and AF. Unfortunately, how the heritable defects of emerin caused the electrical instability in atria was not fully investigated (31). Recently, there were some reports on the mutations in the SCN5A gene, encoding the a-subunit of the cardiac Naþ channel, Nav1.5, which was believed to result in several lifethreatening arrhythmias such as SND, conduction disorder, and ventricular tachycardia (32,33). Ziyadeh-Isleem et al. (34) revealed that the distal truncated SCN5A mutant caused a 70% reduction in INa density to lead to SND and atrial arrhythmias (34). In another recent clinical study of Duhme et al. (35), the authors screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively
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Figure 1. The potential mechanisms between sinus node dysfunction and atrial fibrillation.
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charged lysine 530 with an asparagine (HCN4-K530N) in a highly conserved region of the C-linker, leading to an increased inhibition of activity in heteromeric channels. Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia-bradycardia syndrome and persistent AF (35). The common genetic mutation between SND and AF may be another pivotal link between them, which still needs to be furthered studied. In conclusion, recent evidence has revealed the possible links between SND and AF in clinical, cellular and molecular level, from small and large animal models to humans (Figure 1). A better understanding on the mechanisms between SND and AF from a genetic and molecular standpoint will lead to the breakthrough of recognition on their relationship. We hope further studies will help find future novel therapeutic targets for SND and AF.
Conflicts of Interest None.
Financial Disclosures None.
Acknowledgments This work was supported by grants (30900618, 81270245 to T.L.) from the National Natural Science Foundation of China (501100001809).
References 1. Lamas GA, Lee K, Sweeney M, et al. The mode selection trial (MOST) in sinus node dysfunction: design, rationale, and baseline characteristics of the first 1000 patients. Am Heart J 2000;140:541e551. 2. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs: electrophysiological remodeling. Circulation 1996;94:2953e2960. 3. Chang HY, Lin YJ, Lo LW, et al. Sinus node dysfunction in atrial fibrillation patients: the evidence of regional atrial substrate remodeling. Europace 2013;15:205e211. 4. Fedorov VV, Chang R, Glukhov AV, et al. Complex interactions between the sinoatrial node and atrium during reentrant arrhythmias in the canine heart. Circulation 2010;122:782e789. 5. Li G, Liu E, Liu T, et al. Atrial electrical remodeling in a canine model of sinus node dysfunction. Int J Cardiol 2011;146:32e36. 6. Park J, Shim J, Uhm JS, et al. Post-shock sinus node recovery time is an independent predictor of recurrence after catheter ablation of longstanding persistent atrial fibrillation. Int J Cardiol 2013;168:1937e1942. 7. Chung H, Uhm JS, Sung JH, et al. The type of sinus node dysfunction might predict the severity of atrial remodeling and clinical outcome after catheter ablation of atrial fibrillation. Int J Cardiol 2014;172: 487e489. 8. De Sisti A, Leclercq JF, Fiorello P, et al. Electrophysiologic characteristics of the atrium in sinus node dysfunction: atrial refractoriness and conduction. J Cardiovasc Electrophysiol 2000;11:30e33.
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9. Sanders P, Morton JB, Kistler PM, et al. Electrophysiological and electroanatomic characterization of the atria in sinus node disease: evidence of diffuse atrial remodeling. Circulation 2004;109:1514e1522. 10. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008;51:802e809. 11. Kiryu M, Niwano S, Niwano H, et al. Angiotensin II-mediated up-regulation of connective tissue growth factor promotes atrial tissue fibrosis in the canine atrial fibrillation model. Europace 2012;14:1206e1214. 12. Yongjun Q, Huanzhang S, Wenxia Z, et al. From changes in local RAAS to structural remodeling of the left atrium: a beautiful cycle in atrial fibrillation. Herz; 2014;. http://dx.doi.org/10.1007/s00059013-4032-7. 13. Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006;152: 86e92. 14. Belluzzi F, Sernesi L, Preti P, et al. Prevention of recurrent lone atrial fibrillation by the angiotensin-II converting enzyme inhibitor ramipril in normotensive patients. J Am Coll Cardiol 2009;53:24e29. 15. Swaminathan PD, Purohit A, Soni S, et al. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest 2011;121: 3277e3288. 16. Song YB, On YK, Kim JH, et al. The effects of atorvastatin on the occurrence of postoperative atrial fibrillation after off-pump coronary artery bypass grafting surgery. Am Heart J 2008;156:373. 17. Liakopoulos OJ, Choi YH, Kuhn EW, et al. Statins for prevention of atrial fibrillation after cardiac surgery: a systematic literature review. J Thorac Cardiovasc Surg 2009;138:678e686. 18. Chen WT, Krishnan GM, Sood N, et al. Effects of statins on atrial fibrillation after cardiac surgery: a duration- and dose-response meta-analysis. J Thorac Cardiovasc Surg 2010;140:364e372. 19. Marin F, Pascual DA, Roldan V, et al. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol 2006;97:55e60. 20. Yang D, Yuan J, Liu G, et al. Angiotensin receptor blockers and statins could alleviate atrial fibrosis via regulating platelet-derived growth factor/Rac1/nuclear factor-kappa B Axis. Int J Med Sci 2013;10: 812e824. 21. Chandler NJ, Greener ID, Tellez JO, et al. Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker. Circulation 2009;119:1562e1575. 22. Ueda K, Hirano Y, Higashiuesato Y, et al. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet 2009;54:115e121. 23. Baruscotti M, Bottelli G, Milanesi R, et al. HCN-related channelopathies. Pflugers Arch 2010;460:405e415. 24. Yeh YH, Burstein B, Qi XY, et al. Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome. Circulation 2009;119:1576e1585. 25. Bogdanov KY, Vinogradova TM, Lakatta EG. Sinoatrial nodal cell ryanodine receptor and Naþ-Ca2þ exchanger: molecular partners in pacemaker regulation. Circ Res 2001;88:1254e1258. 26. Joung B, Lin SF, Chen Z, et al. Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation. Heart Rhythm 2010;7:88e95. 27. Bagwe S, Berenfeld O, Vaidya D, et al. Altered right atrial excitation and propagation in connexin40 knockout mice. Circulation 2005;112: 2245e2253. 28. Jones SA, Lancaster MK, Boyett MR. Ageing-related changes of connexins and conduction within the sinoatrial node. J Physiol 2004;560: 429e437. 29. Jones SA, Boyett MR, Lancaster MK. Declining into failure: the agedependent loss of the L-type calcium channel within the sinoatrial node. Circulation 2007;115:1183e1190.
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30. Igarashi T, Finet JE, Takeuchi A, et al. Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation 2012;125:216e225. 31. Karst ML, Herron KJ, Olson TM. X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation. J Cardiovasc Electrophysiol 2008;19:510e515. 32. Tan B-H, Iturralde-Torres P, Medeiros-Domingo A, et al. A novel Cterminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia. Cardiovasc Res 2007;76:409e417.
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33. Shy D, Gillet L, Abriel H. Cardiac sodium channel NaV1.5 distribution in myocytes via interacting proteins: the multiple pool model. Biochim Biophys Acta 2013;1833:886e894. 34. Ziyadeh-Isleem A, Clatot J, Duchatelet S, et al. A truncating SCN5A mutation combined with genetic variability causes sick sinus syndrome and early atrial fibrillation. Heart Rhythm 2014;14: 173e178. 35. Duhme N, Schweizer PA, Thomas D, et al. Altered HCN4 channel Clinker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. Eur Heart J 2013;34:2768e2775.
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Archives of Medical Research
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(2014)
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ORIGINAL ARTICLE
Relationship Between Two Arrhythmias: Sinus Node Dysfunction and Atrial Fibrillation Q1
Jun Zhao, Tong Liu, and Guangping Li Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China Received for publication February 12, 2014; accepted April 21, 2014 (ARCMED-D-14-00089).
We reviewed recent advancements in the relationship between sinus node dysfunction (SND) and atrial fibrillation (AF) and propose some underlying mechanisms in regard to ion and molecular aspects. The amount of clinical and animal experiments have proven the structural and electrophysiological remodeling of sinoatrial node (SAN) and atrium may be related significantly between SND and AF. Atrial remodeling was often related to RAS activation. RAS inhibitors and statin, which resist in atrial fibrosis, may be novel strategies to prevent or treat both SND and AF. Besides, funny current (If) and Ca2þ clock mainly contributing to the SAN automaticity may be another link between SND and AF. Gap junctions such as Cx40, Cx43 and Cx45 were proven to participate in both automaticity and conductivity of electrical impulses in SAN and atrial tissue, which was accepted as another link between SND and AF. Common genetic mutations such as the emerin gene, SCN5A gene and HCN4 gene mutation were also the mechanism for the correlation between SND and AF. Ó 2014 IMSS. Published by Elsevier Inc. Key Words: Sinus node dysfunction, Atrial fibrillation, Remodeling.
Both sinus node dysfunction (SND) and atrial fibrillation (AF) are ‘‘hard nuts to crack’’ in clinical practice. Remarkably, the incidence of AF was up to 53% in a previous study including 100 patients with SND (1). Recently, two consecutive studies have indicated that there may be a possible link between these two common arrhythmias. We review recent advancement in the relationship between SND and AF and propose some underlying mechanisms in regard to ion and molecular aspects. Recent studies have supported that the structural and electrophysiological changes of sinoatrial node (SAN) and atrium may be related significantly between SND and AF. First, the structural and electrophysiological remodeling related to AF may be an important substrate of SND. Elvan et al. (2) were the first to confirm that the corrected sinus node recovery time (CSNRT) was prolonged along with the decreasing of the maximal and intrinsic heart rates in the pacing-induced AF canine model, which was related to the occurrence of SAN Address reprint requests to: Guangping Li, MD, PhD, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People’s Republic of China; Phone: þ86-22-88328368; FAX: þ86-22-28261158; E-mail: gp_limail@ yahoo.com.cn
remodeling. In other words, AF increased the susceptibility to SND. A recent observation from Chang et al. (3) seemed to provide further evidence to support the specific electrophysiological changes related to SND in 34 patients with AF. They found that local atrial voltage change near the SAN region was associated with a prolonged sinus node recovery time, a longer right atrial activation time, a decreased voltage of the SAN area, and a slower conduction velocity along the crista terminalis (3). Also, the SAN structure itself may be recognized as a substrate for the macro-reentry participated by neurohormonal activation, which has been regarded as an important basis of maintaining AF. Fedorov et al. (4) demonstrated acetylcholine (Ach) and isoproterenol (Iso) were shown to facilitate the pacing-induced AF/AFL by shortening the SAN and atrial repolarization period. ACh/ Iso was also confirmed to regulate the filtering properties of the sinoatrial conduction pathways by regulating the degree of the entrance block. It reminded us that some electrophysiological changes of SAN in SND may increase the inducibility of AF. Recently, we investigated the inducibility of AF in a canine model of SND. Compared with baseline, the atrial effective refractory periods (ERPs) were shortened following the establishment of the canine SND model. After rapid atrial pacing, atrial ERPs were further decreased
0188-4409/$ - see front matter. Copyright Ó 2014 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2014.04.005 ARCMED1915_proof ■ 10-5-2014 17-11-28
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remarkably, and the dispersion of atrial ERPs measured at different pacing cycle lengths (PCLs) showed significant variations. The average duration and inducibility of AF after SND was increased. It seemed that the decreased automaticity and conductivity of sinus node was associated with the shortening of atrial refractoriness, which may increase the inducibility and duration of AF (5). Obviously, there have been some animal experiments to investigate the link between SND and AF. Recently, several clinical investigations tried to reveal that electro-anatomical remodeling of the atria associates with SND and AF. Park et al. (6) included 117 patients with long-standing persistent AF (L-PeAF) who underwent radiofrequency catheter ablation (RFCA). Post-shock sinus node recovery time was proven to be an independent predictor of clinical recurrence of AF after RFCA. The recent study of Chung et al. (7) consecutively enrolled 319 nonvalvular AF patients with SND and without SND who had undergone RFCA for drug refractory AF to investigate the relationship between the type of SND and AF recurrence after RFCA. They confirmed that AF patients with SND without tachycardia-bradycardia (TB) syndrome suffered significantly more bradycardia compared to both AF patients with SND and with TB or those without SND, which was correlated with severe structural and electrical remodeling of the atria. These results suggest that the type of SND might predict the degree of atrial remodeling and predict the outcome after RFCA of AF (7). In contrast, De Sisti et al. (8) found that the right atrial effective refractory period was not changed significantly in the enrolled patients with SND (8). However, the AERP measurements were performed only at a single site and the control group was not age-matched in their study. As mentioned above, numerous studies are apt to admit the association between SND and AF, no matter which one promotes the other clinically and experimentally. However, the potential mechanism between these two common arrhythmias is not fully understood. Recent remarkable progress in molecular biology gives us some novel understandings. The structural remodeling of atrium and SAN in both SND and AF is mainly referred to as fibrosis (9,10), which may be promoted by the renin-angiotensin system (RAS) activation. There is novel evidence to indicate angiotensin II (Ang II) as another participator in the occurrence of AF and SND, respectively. Ang II was confirmed to upregulate connective tissue growth factor (CTGF) and TGF-b gene expression, which proposed SAN and atrial fibrosis as the important substrate of maintaining AF in a canine model of AF (11). In a recent clinical study, 80 patients scheduled for mitral valve replacement surgery were enrolled, whose tissue samples of the left atrial appendages were obtained to detect the degree of fibrosis. It was shown that local expression of Ang II was increased in AF patients, which was correlated with the duration of AF and the expression of collagen type I. mRNA expressions of the angiotensin type 1 receptor (AT1R) and angiotensin-converting enzyme
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(ACE) genes were observed to be markedly upregulated in AF patients (12). It suggested that the blockers of RAS including the antagonists of AT1R and ACE may be effective drugs to treat AF and prevent atrial fibrosis induced by AF. CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) trials has provided the evidence. It was shown that adding candesartan to conventional congestive heart failure (CHF) therapy in 6379 patients with symptomatic CHF and without a history of AF at enrollment led to a lower incidence of new-onset AF (13). Later, Belluzzi et al. (14) proved that ACE inhibitor was also effective in preventing relapses of lone atrial fibrillation in the absence of hypertension and/or heart disease. Meanwhile, another study attempted to reveal the association of SND with RAS. It was shown that in wild-type mice, Ang II infusion activated NADPH oxidase, leading to increased oxidized calmodulin kinase II (ox-CaMKII), SAN cell oxidative stress, apoptosis, even SND (15). In addition, statin was also recently accepted as a novel strategy to prevent AF. Several retrospective studies (16,17) and meta-analysis of RCTs (18) have reported that statin therapy was associated with a lower incidence of postoperative AF and shorter hospital stay. The study of Marin et al. (19) seemed to reveal the potential mechanism of the antifibrillatory effect of statins. As was reported, statin was associated with increased tissue inhibitor of matrix metalloproteinase-1, which was mainly responsible for degrading collagen type I and III (19). Although there is currently a lack of direct clinical evidence that angiotensin receptor blockers and statins can effectively prevent SND, it is believed that the inhibition of atrial fibrosis is effective to prevent or treat both SND and AF. According to a recent study, both RAS inhibitors and statins could prevent and inhibit atrial fibrosis via regulating platelet-derived growth factor/Rac1/nuclear factor-kappa B axis (20). Thus, inhibitors of RAS and statin may be novel strategies to prevent or treat both SND and AF. Until now, expression of over 120 ion channels and associated proteins within the human sinus node and right atrium has been comprehensively characterized (21). Among them, the funny current (If) and Ca2þ clock mainly contributing to the SAN automaticity have recently been paid more attention. Hyperpolarization-activated inward current If is the mixture consisting of Kþ and Naþ channels modulated by intracellular cyclic nucleotide. If encoded mainly by the HCN2 and HCN4 genes is normally responsible for electrical automaticity in sinus node. Impaired If was confirmed to participate in the occurrence of SND and result in both brady- and tachyarrhythmias (22,23). Furthermore, Yeh et al. (24) provide further evidence in a canine model of AF. It was shown that rapid pacing downregulated SAN HCN2/4 and minK subunit expression to reduce currents If and Iks by 48% in SAN. If played much more significant role than Iks in the prolongation of SAN recovery time. Also, no changes are shown in voltage dependence or kinetics IKr, IcaL, and IcaT (24).
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The Ca2þ clock, triggered by rhythmic spontaneous sarcoplasmic reticulum (SR) Ca2þ release activates Naþ/ Ca2þ exchanger current (INCx) and causes diastolic depolarization as a complementary mechanism of SAN automaticity (25). Thus, it may serve as another possible link between SND and AF. Joung et al. (26) provided direct evidence that Ca2þ clock malfunction at the superior SAN may contribute partially to the SND in a canine model of pacing-induced AF. In detail, they found that isoproterenol-induced late diastolic Cai elevation (LDCAE) was significantly impaired in the superior SAN of dogs with AF, which was associated with obviously reduced type 2 ryanodine receptor (RyR2) expression in the superior SAN. It was only the inability to develop LDCAE in the superior SAN of the dogs with AF that caused the obstacle in acceleration of heart rate (26). Gap junctions may be another possible link between SND and AF, which participate in both automaticity and conductivity of electrical impulses in SAN and atrial tissue. In SAN and atrial tissue, three main connexin (Cx) isoforms have been found: Cx40, Cx43, Cx45. In Cx43 and Cx45 knock-out mice, there is no significant decrease in heart rate, whereas the deletion of Cx40 gene caused the breakthrough activation of pacemaker activity at other locations distant from the SAN (27). However, another recent observation showed that the loss of Cx43 expression decreased the electrical connection in SAN, which may result in SND (28,29). Meanwhile, mutations of genes
coding for connexins in atrial tissue have been considered as a potential substrate in idiopathic AF. A recent study from Igarashi et al. (30) demonstrated that both transgenes of Cx43 and Cx40 improved atrial conduction and prevented AF in Yorkshire swine models (30). However, recent studies did not provide the direct evidence of connexin as another contactor of SND and AF. Further studies are warranted in the near future. In addition, studies on genetics seem to provide additional surprises. In 2008, Karst et al. (31) confirmed that the mutation of the emerin gene encoding the nuclear membrane protein emerin can cause nonsyndromic, X-linked SND and AF in the multigenerational family of malerestricted and asymptomatic SND and AF. Unfortunately, how the heritable defects of emerin caused the electrical instability in atria was not fully investigated (31). Recently, there were some reports on the mutations in the SCN5A gene, encoding the a-subunit of the cardiac Naþ channel, Nav1.5, which was believed to result in several lifethreatening arrhythmias such as SND, conduction disorder, and ventricular tachycardia (32,33). Ziyadeh-Isleem et al. (34) revealed that the distal truncated SCN5A mutant caused a 70% reduction in INa density to lead to SND and atrial arrhythmias (34). In another recent clinical study of Duhme et al. (35), the authors screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively
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Figure 1. The potential mechanisms between sinus node dysfunction and atrial fibrillation.
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charged lysine 530 with an asparagine (HCN4-K530N) in a highly conserved region of the C-linker, leading to an increased inhibition of activity in heteromeric channels. Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia-bradycardia syndrome and persistent AF (35). The common genetic mutation between SND and AF may be another pivotal link between them, which still needs to be furthered studied. In conclusion, recent evidence has revealed the possible links between SND and AF in clinical, cellular and molecular level, from small and large animal models to humans (Figure 1). A better understanding on the mechanisms between SND and AF from a genetic and molecular standpoint will lead to the breakthrough of recognition on their relationship. We hope further studies will help find future novel therapeutic targets for SND and AF.
Conflicts of Interest None.
Financial Disclosures None.
Acknowledgments This work was supported by grants (30900618, 81270245 to T.L.) from the National Natural Science Foundation of China (501100001809).
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