The term "sick sinus syndrome"(SSS) encompasses a variety of conditions caused by sino-atrial node dysfunction. It is characterized by inappropriate sinus bradycardia, sino-atrial block, sinus arrest with or without junctional escape, or chronotropic incompetence, atrial tachyarrhythmias (atrial fibrillation with slow ventricular response), and alternating bradyarrhythmias and tachyarrhythmias. Patients may experience syncope, pre-syncope, palpitations, dizziness, fatigue or vertigo. However, patients often are asymptomatic or have subtle or nonspecific symptoms related to the decreased cardiac output that occurs with the bradyarrhythmias or tachyarrhythmias. The ECG typically shows sinus bradycardia, sinus arrest, and/or sino-atrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in which case it is considered to be a congenital disorder (Benson et al., 2003).
Loss-of-function mutations in the SCN5A gene result in decreased sarcolemmal expression of mutant channel proteins, expression of non-functional channels or gating disturbances (i.e., delayed activation, hyperpolarizing shift in voltage-dependent inactivation) (Benson et al., 2003; Veldkamp et al., 2003; Lei et al., 2008) that reduce myocardial excitability in some forms of congenital SSS [Benson et al., 2003]. Affected individuals also manifest abnormal ventricular depolarization (prolonged QRS) and delayed His-ventricle conduction. The molecular basis for SSS resulting from SCN5A mutations is an exit block at the peripheral sino-atrial node caused by decreased conduction velocity from the central sino-atrial node (Butters et al., 2010). Additionally, impaired sodium channel function may cause a conduction block within the cardiac conduction system, referred to as AV block or bundle branch block (BBB).
Benson et al. (2003) reported 5 children (2 to 9 years of age) with autosomal recessive SSS characterized by sinus bradycardia, absent P waves, atrial inexcitability, prolonged QRS duration, prolonged His-ventricle conduction time, and ventricular escape rhythms. The disorder progressed from bradycardia to atrial inexcitability during the first decade of life, but none of the patients had other evidence of heart disease. Compound heterozygous SCN5A mutations (T220I, P1298L, G1408R, delF1617, R1623X, and R1632H) were found in five individuals from three families, indicating that congenital SSS may, in some families, segregate as a recessive disorder of the cardiac sodium channel. Two mutations (G1408R, R1623X) produce nonfunctional sodium channels; the remaining alleles were functional when expressed heterologously in cultured mammalian cells and exhibited impaired inactivation and slowed recovery from inactivation. Three mutations exhibited mild to moderate dysfunction (T220I, P1298L, delF1617), while the R1632H allele was more severely impaired. Heterozygous SCN5A mutations (T220I, P1298L, delF1617) occur in patients diagnosed with congenital SSS during the first decade of life, suggesting that congenital SSS segregates as a recessive disorder of the cardiacNa+ channel.
The SCN5A E161K mutation was identified in two non-related families with symptoms of bradycardia, sino-atrial node dysfunction, generalized conduction disease and BrS, or combinations thereof (Smits et al., 2005). The mutation causes a marked reduction in INa density and a positive shift of the voltage-dependence of activation leading to atrial and ventricular conduction slowing and bradycardia by slowing the diastolic depolarization rate and dereasing the upstroke velocity of the sino-atrial action potentials. Both a negative shift in voltage-dependent inactivation and a positive shift in voltage-dependent activation result in narrowing of the INa current window. These finding suggests that a loss ofNa+ channel function is not only associated with BrS and PCCD, but may also cause SSS. A novel SCN5A missense mutation (R878C) located in domain II S5-S6 of the cardiacNa+ channel present in three generations of a Chinese family is associated with clinical phenotypes that include ECG features of slowed atrioventricular conduction, SSS, and ST elevations in the V1 and V2 leads (Zhang et al., 2008). R878C mutant channels shows no detectable INa. The SSS is transmitted as an autosomal dominant or recessive trait, and even a digenic inheritance of a heterozygous SCN5A mutation (D1275N) and a specific haplotype in the connexin-40 promoter has been described in patients with sinus bradycardia, sinus arrest with or without junctional escape, sino-atrial exit block, ectopic atrial bradycardia, and atrial fibrillation with slow ventricular response an onset of atrial bradycardia, atrial standstill and a prolonged His-ventricle conduction time (Groenewegen et al., 2003). Failure of the SCN5A allele alone to confer a clinical phenotype supported an argument favoring a digenic inheritance (Benson et al., 2003). Interestingly, the identified mutations responsible for SSS are all located at positions of trans-membrane segments or extracellular links although they occur in all four domains in contrast to the locations of LQT mutations.
In some patients SSS and PCCD can coexist and are associated cardiomyopathy (i.e., dilated cardiomyopathy associated with mutations in lamin A/C). Similarly, some patients with LQTS3 and BrS present bradycardia and sinus pauses (Makiyama et al., 2005; Veldkamp et al., 2003). It is not a surprise that SSS appears in carriers of loss-of-function mutations in the SCN5A gene (i.e., BrS and PCCD) (Lei et al., 2008; Makiyama et al., 2005; Smits et al., 2005). The inhibition of the INa decreases cardiac excitability and conduction block through the peripheral portion of the sino-atrial node to the surrounding atrial tissue.
Veldkamp et al (2003) studied a gain-of-function (1795insD) mutation associated with sinus bradycardia and sinus pauses together with phenotypic characteristics of LQTS3. The mutation produced a persistent INa (INaL) over the voltage range traversed by the SA node action potential and a negative shift in voltage-dependence of inactivation. This latter effect reduce INa during the diastolic depolarization phase, thereby reducing sinus rate, while the increase in INaL prolongs the APD. Thus,Na+ channel mutations displaying a INaL or a negative shift in inactivation may account for the bradycardia observed in LQT3 patients, while sino-atrial pauses or arrest may result from failure of SA node cell to repolarize under conditions of extra net inward current. In fact, in patients with LQT3 SCN5A mutations in which the INaL is accompanied by a negative shift in inactivation, sinus bradycardia is aggravated. The expression of SCN5A is restricted to the peripheral SA node, but is absent in the central SA node. However, simulations with SCN5A mutations show that mutants slow sinus rate within the sino-atrial node. The atria imposes a significant hyperpolarizing load on the sino-atrial node, which is counterbalanced by SCN5A expression in peripheral cells. Thus, reduced INa in the peripheral sino-atrial nodal cells exposes the central SA node to moe hyperpolarizined potentials, reducing the pacemaking rate.
Both loss- and gain-of-function SCN5A mutations and ageing may slow pacemaking rates and affect conduction to surrounding atrial tissue by promoting tissue degeneration via transforming growth factor (TGF)-β1–mediated fibrosis (Hao et al., 2011).
The SSS is also associated with mutations of the HCN4 gene encoding the K+/Na+ hyperpolarization-activated cyclic nucleotide-gated channel 4 that generates the pacemaker current (If) in the sino-atrial node cells. A frameshift HCN4 mutation (HCN4-573X) encoding a truncated C-terminus channel lacking the cytoplasmic tail including the cyclic nucleotide-binding domain (CNBD) was described in a patient with bradycardia and a defective response of heart rate to exercise (chronotropic incompetence) without prolongation of QT interval (Schulze-Bahr et al., 2003). Residue 573 is in the C-linker, so that mutated proteins lack the cyclic nucleotide-binding domain and therefore, mutated channels did not respond to cAMP. A missense mutation (D553N) was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation and polymorphic VT but did not cause any shift in the voltage dependence of activation (Ueda et al., 2004). Co-expression of mutant channels reduced the cell surface expression of normal channels in a dominant-negative manner. The mutations S672R and G480Rlocated in the CNBD does not affect cAMP-induced channel activation, but shifted the current activation range to hyperpolarized voltages and slowed current deactivation. These changes led to a reduced If during diastolic depolarization and hence slowed the heart rate (Milanesi et al., 2006; Nof et al., 2007). Mutation A485V, located in the loop connecting P to S6 was associated with dizziness, presyncopal episodes and cardiac arrest (Laish-Farkash et al. 2010). The mutation produces adecrease in the synthesis and membrane expression of channel protein, with no change in ion selectivity, and a negative shift of the voltage range of current activation.
Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, Holm et al (2011) identified the MYH6 gene, encoding the alpha heavy chain subunit of cardiac myosin, as a sick sinus syndrome susceptibility gene. A missense (Arg721Trp) has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome (OR 12.53).
Table. Genetic loci and genes associated with the Sick sinus syndrome
The treatment of congenital SSS includes the correction/removal of extrinsic causes (i.e., that can provoke sinus bradyarrhythmias). Specific treatment for the control of symptomatic SSS usually involves the implantation of a pacemaker. Acute treatment consists of atropine (0.04 mg/kg IV every 2-4 h) and/or isoproterenol (0.05-0.5 mcg/kg/min IV). Because both bradyarrhythmias and tachyarrhythmias may be present and drugs to control tachyarrhythmia may exacerbate bradyarrhythmia, patients should be monitored closely to ensure that the bradyarrhythmias are not exacerbated or causing symptoms (eg, dizziness, syncope, congestive heart failure); if exacerbation of arrhythmias or symptoms occur, permanent pacemaker therapy is also required.
Benson DW, Wang DW, Dyment M, et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003;112:1019-1028.
Butters T.D., Aslanidi O.V., Inada S. Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome. Circ Res. 2010;107:126–137.
Groenewegen WA, Firouzi M, et al. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res 2003;92:14-22.
Hao X, Zhang Y, Zhang X, et al. TGF-β1-mediated fibrosis and ion channel remodeling are kay mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging. Circ Arrhythm Electrophysiol. 2011;4:397-406.
Holm H, Gudbjartsson DF, Sulem P, et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nature Genet. 2011;43: 316-320.
Kodama T, Serio A, Disertori M, et al. Autosomal recessive paediatric sick sinus syndrome associated with novel compound mutations in SCN5A. Int J Cardiol. 2013;167:3078–3080.
Kruse M, Schulze-Bahr E, Corfield V, et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest. 2009;11:2737-44.
Lei M, Huang CL, Zhang Y. Genetic Na+ channelopathies and sinus node dysfunction. Prog Biophys Mol Biol. 2008;98:171-178.
Laish-Farkash A, Glikson M, Brass D, et al. A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. J Cardiovasc Electrophysiol. 2010; 21:1365-72.
Makita N, Sasaki K, Groenewegen WA, et al. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms. Heart Rhythm 2005;2:1128.
Makiyama T, Akao M, Tsuji K, et al. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol 2005;46:2100-2106.
Milanesi R, Baruscotti M, Gnecchi-Rusconi T et al. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006;354:151-157.
Nof E, Luria D, Brass D, et al. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation. 2007; 116:463-70.
Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest. 2003;111:1537-45.
Smits JP, Koopmann TT, Wilders R, et al. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J Mol Cell Cardiol 2005;38:969–81.
Ueda K, Nakamura K, Hayashi T, et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004;279:27194-8.
Veldkamp MW, Wilders R, Baartscheer A, et al. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families. Circ Res 2003;92:976-983.
Zhang Y, Wang T, Ma A, et al. Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel. Acta Physiol (Oxf) 2008;194:311-323.
