© 2003 by European Society of Cardiology
REVIEW
The implications of genetic mutations in the sodium channel gene (SCN5A)
1Department of Molecular Biology, Biochemistry and Biopharmacy, Medical University of Silesia ul. Narcyzów 1, Sosnowiec, Poland;
2I Department of Cardiology, Medical University of Silesia ul. Zio
owa 45/47, 40-635 Katowice, Poland
Manuscript submitted 4 February 2003. Accepted after revision 22 June 2003.
Correspondence: Ewa Moric, PhD, Department of Molecular Biology, Biochemistry and Biopharmacy, Medical University of Silesia, ul. Narcyzów 1, 41-200 Sosnowiec, Poland. Tel.: +48-32-291-43-93x54; Fax: +48-32-291-74-66. E-mail: e.moric{at}poczta.clinika.pl; bulba2{at}wp.pl
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Abstract |
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 Top Abstract BackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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Mutations in sodium channel
-subunit gene (SCN5A) result in multiple arrhythmic syndromes, including long QT3 (LQT3), Brugada syndrome (BS), an inherited cardiac conduction defect, sudden unexpected nocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS), constituting a spectrum of disease entities termed Na+ channelopathies. These diseases are allelic disorders, if not the same disease with variable penetrance and variable modifiers worldwide. Interestingly, death occurs during sleep in all of these disorders, suggesting a common mechanism. To date, mutational analyses have revealed about 103 distinct mutations in SCN5A, of which at least more than 30 mutations are associated with LQT3, whereas the rest of the mutations are affiliated with the remaining sodium channel disorders. The majority of these mutations are missense. However, other types such as deletions, insertions, frameshifts, nonsense and splice-donor errors have also been reported.
Key Words: Arrhythmia, Brugada syndrome, long QT3 syndrome, SCN5A gene, sodium channel, mutation
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Background |
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TopAbstractBackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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The heterozygous mutations in the cardiac voltage-gated sodium channel
-subunit gene (SCN5A) have been implicated in rare, familial types of cardiac arrhythmogenic disorder, involving long QT syndrome variant type 3 or LQT3[1]
, Brugada syndrome (BS)[2,3] and progressive cardiac conduction defect (PCCD) otherwise known as Lev–Lenegre disease syndrome[4].
Recently, Splawski et al.[5] identified a variant of the cardiac sodium channel gene that is associated with arrhythmia in African–Americans and linked it with risk of arrhythmia in an African–American family. The variant allele termed Y1102 is responsible for accelerating channel activation, thereby enhancing the probability of cardiac arrhythmias in persons of African descent. Though the variant gene is not likely to cause problems on its own as emphasized by the authors, it may be induced or triggered by other factors to be pathogenic.
The BS is the mirror image of LQT3 and both are known to share the same position or locus on a specific chromosome in the diploid cells (3p24–p21). For this reason, they are regarded as allelic diseases, differing slightly in mutations in the amino acid sequence in the Na+ channel of the sarcolemma (‘channelopathies’).
The loss of function of cardiac sodium channels, either by reducing expression levels or by increasing its inactivation kinetics, is the main pathological origin of the BS[6,7], whereas the mutation of LQT3 is associated with a gain of function mechanism with a slow and constant entry of Na+ in phase 2 (prolonged inactivated), which, in turn, increases the duration of the ST segment leading to a prolonged QTc at the expense of ST, altogether resulting in late appearance of the T wave.
Yan and Antzelevitch[8] have proposed a mechanism for the ST segment shift and the occurrence of ventricular fibrillation in BS. The proposed mechanism per se is consistent with observations that the characteristic ECG pattern may be precipitated in patients with the latent syndrome by administration of sodium channel blocking drugs.
Mixed electrocardiographic features have been reported in a large family with SCN5A mutations showing elevation of ST segment and prolonged QTc. In certain cases, the production of ST-segment elevation by flecainide has raised the question whether BS and LQT3 could be two aspects of the same disease[9].
Besides the genetic similarity between BS and LQT3, both diseases exhibit very different clinical ECG features but show coincidences that emanate from their common genetic root. It is not yet clear why the ECG pattern of affected individuals with BS vary from day to day and why most affected persons are males. Sex and hormonal differences in ion channel distribution have been described in the heart and could cause alterations in disease penetrance[10]. It is also not known if other clinical conditions that cause ST or J-point elevation (ischaemia, hypothermia, acidosis) can cause arrhythmias by mechanisms similar to BS. Future studies may shed more light on this.
Vatta et al.[11] have reported that the clinical features of sudden unexplained nocturnal death syndrome (SUNDS), which is a disorder particularly found among males in Southeast Asia, are genotypically, phenotypically and functionally identical to BS. The authors also speculated that both SUNDS and BS could be allelic disorders or even the same disease.
In this review, we shall focus on the SCN5A gene mutations and summarize current information on therapeutic consequences associated with disorders of this gene.
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Mutations in the SCN5A gene |
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TopAbstractBackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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Inherited mutations in SCN5A, the gene encoding the human cardiac sodium channel, have been linked with varied disorders of cardiac rhythm that range from rapid, life-threatening tachyarrhythmias to bradyarrhythmias[12]
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The SCN5A gene consists of 28 exons and encodes a protein of 2016 amino acids, with a calculated molecular mass of 227 kDa[13]. The cardiac Na+ channel -subunit is composed of four homologous domains, DI–DIV (Fig. 1). Each domain comprises six transmembrane segments of which the S4 segments are believed to function as voltage sensors. Little is known about the structure of the C-terminus of the SCN5A gene, but disease associated mutations within this 244 amino acid intracellular region of the channel have recently been reported to play a significant role in channel inactivation and stabilization of the inactivated state[14]. SCN5A is highly expressed in human myocardium but not in skeletal muscle, liver or uterus. However, it has also been reported to be expressed in the brain[15].
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Mutations in the SCN5A gene have been identified in families from all over the world. Missense mutation, a splice-donor mutation and a frameshift mutation in the coding region of SCN5A have been reported. The first two are responsible for the quick recovery of the Na+ channel from the inactivated state, and the frameshift mutation produces lack of functioning of the channel, which causes the heterogeneous loss of the ‘plateau’, dome or phase 2, only in the right ventricular epicardium but not in the endocardium (precisely adjacent to leads V1–V3)[2]
. Other functional consequences of missense mutation in the SCN5A include enhancement of slower forms of inactivation[16], which is expected to cause an activity-dependent loss of sodium channel availability, resulting in reduced sodium current density[17]. Shifts in the voltage dependence of activation and inactivation have also been reported[18].
In 1995, Wang et al.[19] described deletion in nine nucleotide bases, resulting in the loss of three amino acids in the protein channel: lysine (K), proline (P) and glutamine (Q). This mutation known as 
KPQ is linked with LQT3 in four different families.
Three other LQT3 mutations were reported in asparagine, at position 1325, exchanged by serine (N1325S), arginine at position 1644 is exchanged by histidine (R1644H) and finally another one in the residue 1623 (R1623Q) in the S4 segments of domains III and IV of the Na+ channel[20]. Kambouris et al.[21] reported that the R1623Q mutation imparts unusual lidocaine sensitivity to the sodium channel that is attributable to its malfunctional behaviour.
A highly conserved acidic domain in the C-terminus appears to be a ‘hotspot’ for LQT3 mutations. In the C-terminus, two charge-altering LQT3 mutations (E1784K, 1795insD) have been reported to evoke small, sustained currents similar to KPQ[17,22], while a third charge deletion (D1790G) produces both a small plateau[23] and alters the voltage dependence of inactivation in a pro-arrhythmic manner[24].
Mutations in the SCN5A gene that segregated and co-segregated with PCCD in an autosomal dominant manner have been reported. In the Dutch family, frameshift mutation co-segregated with familial non-progressive conduction defect, while PCCD was identified in the French family through a member with right bundle branch block (RBBB) associated with donor splice site mutation. Therefore, PCCD represents a third cardiac disorder linked with SCN5A[4].
Several mutations linked to BS have been described in SCN5A, the only gene hitherto associated with the disorder in chromosome 3p21[25]. The theory proposed by Yan and Antzelevitch[8] states that a decrease in the depolarizing inward sodium current is thought to lead to early repolarization in the right ventricular epicardium, where the transient outward K+ current (Ito) is large. This would cause a voltage gradient from endocardium to epicardium, ST elevation on the ECG and susceptibility to arrhythmias caused by phase 2 reentry.
Using sequencing analysis, Nissenbaum et al.[26] reported two mutations, G35S and R104Q in two Brugada patients and a possible R34C polymorphism in two unrelated controls, and went further to suggest genetic heterogeneity, as no mutations were detected in five other patients studied.
Molecular biological analysis can document SCN5A gene mutations in 15–25% of patients with BS. Although the prevalence of SCN5A mutations among BS patients is not known precisely, a study showed that the prevalence of SCN5A defects among 84 genotyped patients clinically affected by BS is approximately 20–25%, representing the largest series of carriers of SCN5A mutations reported in literature[27].
Schwartz et al.[28] described an infant who nearly died of sudden infant death syndrome (SIDS), whose parents had normal QT intervals and in whom the long QT syndrome was diagnosed with identification of a spontaneous mutation of the SCN5A gene: a change of codon 941 from TCC (serine) to ACC (asparagine).
On the other hand, Tan et al.[29] studied a family who came for medical attention when the proband, a 3-year-old girl, experienced episodes of fainting during a febrile illness. All affected family members had a G-to-T transversion in the first nucleotide of codon 514 in exon 12 of the SCN5A gene resulting in the replacement of glycine by cysteine (G514C). Computational analysis predicts that the gating defects of G514C selectively slow down myocardial conduction, but do not provoke the rapid cardiac arrhythmias previously associated with SCN5A mutations.
Weiss et al.[30] described a large multigenerational family (12 affected individuals) with an autosomal dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age and sex. Eleven of the 12 affected individuals were males, and linkage to a locus on chromosome 3p22–25 quite distinct from SCN5A is identified, confirming genetic heterogeneity of the disorder.
However, studies by Smits et al.[31] have shown that the region on chromosome 3 (3p22–25) linked to BS appears to contain no modulatory subunits of the sodium channel, the pore-forming and modulatory components of the transient outward current, the L-type calcium current or ion channel components that could represent homologues of these proteins. The presence of conduction defects, as evidenced by a prolonged His to ventricle interval (HV) and PQ interval at baseline, and excessive QRS interval prolongation after Na+ channel blockade are more likely to be seen in BS patients who are carriers of SCN5A mutation[31].
Wang et al.[32] reported a family in which the proband had presented with first-degree atrioventricular block at the age of 9 years, progressing to complete AV block by the age of 20 years, and also another child in whom second-degree AV block had been diagnosed at the age of 6 years, progressing to complete AV block by the age of 12 years. Sequencing of the coding region of SCN5A revealed a substitution of serine for glycine (G298S) in the domain I S5–S6 loop and asparagine for aspartic acid (D1595N) within the S3 segment of domain IV. Both mutations are known to impair fast inactivation but do not exhibit sustained non-inactivating currents. The mutations also reduce sodium current density and enhance slower inactivation components. The summary of gene mutations associated with SCN5A gene is given in Table 1.
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Clinical features associated with SCN5A gene |
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TopAbstractBackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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Mutations in SCN5A lead to a broad spectrum of phenotypes, including long QT syndrome, BS, SIDS (probably regarded as a form of LQT3), SUNDS and isolated PCCD (Lev–Lenegre disease)[2,
4,28,38]. SCN5A mutations have been identified in the patients diagnosed as having this disorder, thus confirming that SUNDS and BS are the same clinical entity. SCN5A seems to play different kinds of roles, leading in an apparent ‘split personality’ clinically. Interestingly, death most commonly occurs during sleep in all of these disorders, suggesting a common mechanism.
Initially, mutations of the cardiac sodium channel gene SCN5A were identified as a cause of a rare variant of long QT syndrome, so called LQT3. The LQT3 accounts for approximately 5–10% of the genotyped LQT families. This is characterized by prolongation of repolarization and ventricular polymorphic tachycardia, so called torsade de pointes, which may lead to sudden cardiac death (SCD). Exercise-related episodes (typically during swimming) dominate in LQT1, while rest or sleep related events are more common in LQT3[57]. In contrast to LQT1, LQT3 patients are also at risk of the onset of cardiac events later in life.
BS also is a familial disease which is often characterized by syncope or SCD as the only symptom among its patients. In some cases, sudden death is the first symptom of the disease. Monitoring of BS patients has shown the polymorphic ventricular tachycardias (VTs) as the underlying cause[58]. VT usually begins with a short coupling interval and self-terminating episodes typically result in recurrent episodes of syncope. About 80% of victims of cardiac arrest associated with BS had experienced a syncopal event[59]. Clinical reports signify that sudden death in patients with BS occurs mostly during sleep, especially late at night. Fever has been reported as a possible risk factor for cardiac arrest. The mean age at which symptoms first appear in affected individuals is the third to fourth decade of life. However, symptomatic twins at 1 year of age have been reported[60,61].
BS may occur with a peculiar high prevalence in the Far East countries where it is suspected to constitute a major cause of sudden death among young individuals and the cause of SUNDS[11]. The clinical features and electrocardiographic findings of SUNDS, a disorder found in Southeast Asia, particularly Thailand, Japan, Philippines and Cambodia[11], are similar to those of BS. The sex-related difference in the phenotypic expression of BS is more pronounced than that in any other autosomally transmitted arrhythmic syndrome. Although the genotype is transmitted in equal proportion to males and females, the manifestation of the clinical syndrome is observed 
10 times more often in males than in females. This low penetrance of the disease in females led to the Southeast Asian custom of men dressing in women's clothes at bedtime to fool the ‘evil spirits’ that were presumed to target males in their sleep. The basis for this disparity between the sexes has long defied explanation[62–65].
More recently, Tan et al.[29] demonstrated that mutations in SCN5A cause complete AV block in some patients, resulting in bradycardia-induced symptoms, which suggest that cardiac conduction system abnormalities may exist in some cases. Patients with typical isolated cardiac conduction defect (ICCD) do not show ECG characteristics of BS and also do not respond positively to flecainide challenge used as a provocative test.
Expression studies revealed the existence of silent mutated channels but normal intracellular trafficking. Kyndt et al.[42] have raised the possibility that the consequence of the same SCN5A mutation may be individual-specific or, precisely, branch-specific. The authors also reported that the same SCN5A mutation can lead to two different ECG phenotypes and, thereafter, to different syndromes and, most importantly, different risks, i.e. tachyarrhythmia or inversely extreme bradycardia, depending on the family collateral branch. Sex differences may be related to genetic factors influencing phenotype. Thus, it is conceivable that sex can influence the phenotype via the effects of sex hormones on repolarizing potassium currents. This hypothesis still requires further evaluation[42].
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ECG findings |
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TopAbstractBackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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LQT3
Moss[66]
showed that the ECG manifestations of LQTS were determined by the mutated gene. The ECG of LQT3 is associated with unusually increased duration of the ST segment leading to a prolonged QTc at the expense of ST, altogether with the late appearance of the T wave. Zhang et al.[67] identified in patients with LQT3 late-onset peaked/biphasic T wave and asymmetric peaked T wave. However, rate-corrected QT interval duration did not differ among LQT1, LQT2 and LQT3 patients[68] and overlap existed among the repolarization patterns of LQT1, LQT2 and LQT3, and one-third of LQT3 gene carriers had repolarization similar to those of LQT1 gene carriers. LQT3 patients tend to shorten QT intervals during exercise induced tachycardia and to have significant QT prolongation at long cycle lengths. The cellular mechanism for QT prolongation in most LQT3 is believed to be persistent Na+ current during the action potential plateau attributable to the defects in Na+ channel fast inactivation (gain of function) that delay repolarization. LQT3 patients have a further prolongation of the QT interval at night and are particularly likely to die while at rest or in their sleep, and during their first arrhythmic episode. The administration of sodium channel blockers such as mexiletine shortens the QT interval in these patients and may prevent the arrhythmias. Most notable for LQT3 patients is the long isoelectric segment followed by a normal T-wave duration with a relatively sharp deflection (present in 82% of LQT3 patients with a typical ST–T wave pattern).
BS
The electrocardiographic feature of BS is ST-segment elevation in the right precordial leads which is dynamic and often concealed. Three types of ECG abnormalities are recognized[58]. Type 1 is characterized by a prominent coved ST-segment elevation displaying J-wave amplitude or ST-segment elevation 
2 mm or 0.2 mV at its peak followed by a negative T wave. Type 2 has a high take-off ST-segment elevation and wave amplitude (2 mm) gives rise to a gradually descending ST-segment elevation, followed by a positive or biphasic T wave. This results in a saddle back configuration. Type 3 is a right precordial ST-segment elevation of 
1 mm of saddle back type, coved type, or both. The absence of S waves in the left lateral leads precludes the true presence of RBBB.
No reciprocal ST-segment depression is noted in most cases. In selected subjects alternative higher intercostals space V1 to V3 lead ECG could be helpful in detecting BS patients. The PR interval is often increased due to the presence of HV prolongation and other conduction disorders such as left anterior hemiblock and RBBB are present. About 10% of BS patients have concomitant atrial fibrillation. Preliminary evidence suggested the existence of a variant of BS associated with ST elevation in the inferior leads. Intermittent nature of ECG findings can make diagnosis of BS difficult. Sodium channel blocking agents such as ajmaline, procainamide, flecainide and propafenone can provoke or accentuate the ST changes and are used in diagnostic tests. SUNDS shares the same ECG pattern as BS.
Smits et al.[31] tested a genotype–phenotype relationship in BS patients and showed that the presence of conduction defects (prolonged HV and PQ) at baseline and excessive QRS interval prolongation after sodium channel blockers are more likely found in BS patients who are carriers of an SCN5A mutation.
It is well known that ST segment varies day by day, and so may be an inadequate indicator of BS. In order to distinguish the normal ST-segment elevation observed in athletes from that of BS, the magnitude of the ST elevation and the QRS duration may be useful. Therefore, not only ST elevation, but also the S wave width should be measured to detect high-risk patients.
PCCD
PCCD is characterized by progressive slowing of cardiac conduction velocity through the His–Purkinje system with right or left bundle branch block and widening of QRS complexes. Relatively little information is available concerning the spectrum of genetic defects, the clinical manifestations and the genetic epidemiology of PCCD. Presently, it is not possible to delineate fully the picture of this form of cardiac sodium channel disorder.
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Risk stratification |
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TopAbstractBackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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The genetic defects on the cardiac sodium channel gene linked with the LQT3 are associated with higher risk of SCD[57]
. Cardiac arrhythmias are significantly more frequent among patients with LQT1 and LQT2, while lethal events are more frequent in those with LQT3[68]. The higher lethal nature of cardiac events in patients with mutations at the LQT3 locus may contribute to a potential under-representation of such patients among patients with a diagnosis of LQTS. Risk stratification is mainly based on history of syncope, torsade de pointes or cardiac arrest[69]. The duration of the corrected QT interval or macroscopic T wave alternans are weaker predictors of SCD.
The risk stratification in BS is still undefined[35,70]. The mortality in symptomatic patients averages 10% per year. Asymptomatic patients appear to have a better prognosis. It is not known how to identify those individuals who at the moment are asymptomatic but may become symptomatic in the future. Ikeda et al.[71] assessed various noninvasive markers in identifying patients at risk in BS. There was no relationship between the magnitude of J-point elevation at rest and life-threatening events. However, it has been shown that detection of late potentials was a useful stratifier predicting life-threatening arrhythmic events.
Ventricular arrhythmia inducibility in BS patients, at variance with healthy controls, is high (50–80%) but does not correlate with clinical presentation[72]. Results are deeply influenced by the protocol used[73]. In Consensus Report the Study Group on the Molecular Basis of Arrhythmias of the European Society of Cardiology experts in this field suggested a protocol using two stimulation sites using at least three cycle lengths 1–3 extrastimuli and a minimal coupling interval of 200 ms[58].
Data reported by Brugada et al.[74] have shown a low positive predictive value of PES (13%) but a good predictive value of PES in asymptomatic non-inducible individuals (99%). In contrast to this study, Priori et al.[35] reported a low positive (50%) and negative (46%) predictive value. PES results have been reported at mid-term observation to have poor correlation with the incidence of arrhythmic events. However, this does not exclude the possibility of correlation with long-term follow-up[75]. Before drawing any conclusion on the value of PES in BS, data on a large population of patients studied with the same protocol and with a longer follow-up are required. It seems that asymptomatic patients with Brugada ECG pattern and negative family history are not candidates for PES.
Priori et al.[59] evaluated the natural history of BS in a large cohort of 200 patients including the largest worldwide population of genotyped individuals. High-risk patients (10%) presented a baseline ST-segment elevation and had history of syncope. Forty-four percent of them had cardiac arrest. Patients with intermediate risk (41%) had spontaneous ST-segment elevation 2 mm without history of syncope and presented a strong trend toward an increased risk that fails to reach statistical significance. Lastly, patients with a negative phenotype (silent mutation carriers) or who have a diagnostic ECG only after provocative test were at lower risk of cardiac events. No study has shown the impact of genetic analysis on risk stratification of the syndrome.
Splawski et al.[5] recently identified a common SCN5A variant in Africans and African–Americans, which causes a small but inherent and chronic risk of acquired arrhythmia. The identification of the variant allele known as Y1102 causes a subtle increase in the risk of life-threatening arrhythmias and prevention could be facilitated through rapid identifications of individuals at risk. However, most of these individuals will never have an arrhythmia because the effect of Y1102 is subtle[5].
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Management |
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TopAbstractBackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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Knowledge about the mutations causing LQT syndrome has initiated research on the therapies targeted at the mutant ion channels. Adjustment of lifestyle is of vital importance in the prevention of SCD in all categories of patients with LQT (symptomatic, asymptomatic and silent carriers of the genetic defect)[59]
. However, while this is extremely important for LQT1 patients, some degree of flexibility for non-competitive physical activity may not have to be withheld, except for persons who have already experienced episodes during exercise[68]. All patients must avoid the use of drugs that prolong QT.
The percentage of patients who were free of recurrence with beta-blocker therapy was higher and the death rate lower among LQT1 patients (81% and 4%, respectively) than among LQT3 (50% and 17%, respectively) patients[68]. LQT3 patients are at higher risk at longer cycle lengths. Therefore, they may benefit more from pacemaker implantation, which allows the safe use of beta-blockers[68,76]. In addition, selective left cardiac sympathetic denervation, which does not reduce heart rate, may be more effective in LQT3 symptomatic patients with recurrences on beta-blockers. Implanted cardioverter defibrillator (ICD) implantation is recommended in survivors of cardiac arrest. The use of beta-blockers should be continued along with the implantation of an ICD.
The sodium channel blockers flecainide and mexiletine have been reported beneficial in the LQT3[77]. The extent to which these agents may be effective in preventing SCD is not yet known. At present, these drugs may be considered only as adjuncts to the standard therapy.
BS survivors of cardiac arrest and patients with a history of syncope, VT or a family history of juvenile SCD should receive an ICD[69]. Management of asymptomatic patients is still undetermined and debated. Silent mutation carriers and patients who have BS ECG pattern only after provocative test should be reassured[27] and educated about symptoms and the need for reevaluation. Sodium channel blocking agents and tricyclic antidepressants should be avoided[78]. Caution should be exercised when using alpha-agonists or neostigmine[79]. Antiarrhythmic agents such as beta-blockers and amiodarone are ineffective. Some investigators advocate quinidine[80].
In summary, it should be noted that SUNDS, BS, SIDS, LQT3 and conduction system diseases are allelic disorders, if not the same disease with variable penetrance and variable modifiers worldwide. Subclinical mutations associated with the SCN5A gene may predispose the subset of individuals to life-threatening arrhythmias in the course of drug therapy.
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References |
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TopAbstractBackgroundMutations in the SCN5A...Clinical features associated...ECG findingsRisk stratificationManagementReferences |
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