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Long-QT Syndrome

2012; Lippincott Williams & Wilkins; Volume: 5; Issue: 4 Linguagem: Inglês

10.1161/circep.111.962019

1941-3149

Peter J. Schwartz, Lia Crotti, Roberto Insolia,

Receptor Mechanisms and Signaling

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 5, No. 4Long-QT Syndrome Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBLong-QT SyndromeFrom Genetics to Management Peter J. Schwartz, MD, Lia Crotti, MD, PhD and Roberto Insolia, PhD Peter J. SchwartzPeter J. Schwartz From the Department of Molecular Medicine, University of Pavia, Pavia, Italy (P.J.S., L.C., R.I.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (P.J.S., L.C., R.I.); Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town (P.J.S.); Department of Medicine, University of Stellenbosch, Stellenbosch, South Africa (P.J.S.); Chair of Sudden Death, Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia (P.J.S.); and Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.). , Lia CrottiLia Crotti From the Department of Molecular Medicine, University of Pavia, Pavia, Italy (P.J.S., L.C., R.I.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (P.J.S., L.C., R.I.); Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town (P.J.S.); Department of Medicine, University of Stellenbosch, Stellenbosch, South Africa (P.J.S.); Chair of Sudden Death, Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia (P.J.S.); and Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.). and Roberto InsoliaRoberto Insolia From the Department of Molecular Medicine, University of Pavia, Pavia, Italy (P.J.S., L.C., R.I.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (P.J.S., L.C., R.I.); Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town (P.J.S.); Department of Medicine, University of Stellenbosch, Stellenbosch, South Africa (P.J.S.); Chair of Sudden Death, Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia (P.J.S.); and Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.). Originally published1 Aug 2012https://doi.org/10.1161/CIRCEP.111.962019Circulation: Arrhythmia and Electrophysiology. 2012;5:868–877is corrected byCorrectionIntroductionThe congenital long-QT syndrome (LQTS) is a life-threatening cardiac arrhythmia syndrome that represents a leading cause of sudden death in the young. LQTS is typically characterized by a prolongation of the QT interval on the ECG and by the occurrence of syncope or cardiac arrest, mainly precipitated by emotional or physical stress.Since 1975,1 2 hereditary variants, the Romano-Ward (RW) syndrome2,3 and the extremely severe Jervell and Lange-Nielsen (JLN) syndrome,4,5 which is associated with congenital deafness, have been included under the comprehensive name of LQTS, one of the best understood monogenic diseases. The usual mode of inheritance for RW is autosomal dominant, whereas JLN shows autosomal recessive inheritance or sporadic cases of compound heterozygosity.Several reasons make LQTS an important disease. It can often be a lethal disorder, and symptomatic patients left without therapy have a high mortality rate, 21% within 1 year from the first syncope.6 However, with proper treatment, mortality is now ≈1% during a 15-year follow-up.7 This makes inexcusable the existence of symptomatic but undiagnosed patients. LQTS is without doubt the cardiac disease in which molecular biology and genetics have made the greatest progress and unquestionably is the best example of genotype-phenotype correlation. In this regard, it represents a paradigm for sudden cardiac death, and its progressive unraveling helps to better understand the mechanisms underlying sudden death in more complex disorders, such as ischemic heart disease and heart failure.This review will outline the current knowledge about the genetics of LQTS and provide essential clinical data, whereas its primary focus will be on our approach to the clinical management of these patients.Genetics of LQTSThe electrocardiographic QT interval represents the depolarization and the repolarization phases of the cardiac action potential. The interplay of several ion channels determines the action potential duration. Decreases in repolarizing outward K+ currents or increases in depolarizing inward sodium or calcium currents can lead to prolongation of the QT interval, thus representing a pathophysiological substrate for LQTS. Not surprisingly, since the dawn of the molecular era in LQTS, genes encoding ion channels responsible for the timely execution of the cardiac action potential were considered plausible targets for investigation. After the identification of the first 3 genes associated with the most frequent variants,8–10 10 more genes involved in fine-tuning the cardiac action potential have been associated with LQTS (Table 1).Table 1. LQTS GenesGeneSyndromeFrequencyLocusProtein (Functional Effect)KCNQ1 (LQT1)RWS, JLNS40–5511p15.5Kv7.1 (↓)KCNH2 (LQT2)RWS30–457q35–36Kv11.1 (↓)SCN5A (LQT3)RWS5–103p21–p24NaV1.5 (↑)ANKB (LQT4)RWS<1%4q25–q27Ankyrin B (↓)KCNE1 (LQT5)RWS, JLNS<1%21q22.1MinK (↓)KCNE2 (LQT6)RWS<1%21q22.1MiRP1 (↓)KCNJ2 (LQT7)AS<1%17q23Kir2.1 (↓)CACNA1C (LQT8)TS<1%12p13.3L-type calcium channel (↑)CAV3 (LQT9)RWS<1%3p25Caveolin 3 (↓)SCN4B (LQT10)RWS<1%11q23.3Sodium channel-β4 (↓)AKAP9 (LQT11)RWS<1%7q21–q22Yotiao (↓)SNTA1 (LQT12)RWS<1%20q11.2Syntrophin α1 (↓)KCNJ5 (LQT13)RWS 1 phenotype, the so-called overlap syndrome.20 When a single mutation can have opposite functional effects (ie, increase and decrease of the Na+ current), what matters clinically is the phenotype.Given the large and growing number of genetic variants identified so far, to distinguish pathogenic mutations from rare variants is critically important. Based on almost 400 definite cases and 1300 controls,21 the probability for a missense mutation to be pathogenic appears to depend largely on location. In general, genetic variants located in the pore and transmembrane regions are much more likely to be pathogenic. Whenever a functional study of the specific mutation has been performed, the results may help in assessing its clinical relevance. When these data are missing, as is often the case, it is important to establish whether within the family the mutation cosegregates with either symptoms or QT prolongation. An important take-home message is that the laboratory finding of an aminoacidic substitution should not be automatically taken as an indication of a disease-causing mutation.Minor LQTS GenesAfter the identification of the first 3 LQTS genes,8–10 several others were and are being identified; the list will continue to grow for a while.KCNE1 and KCNE2 encode the minimal K+ ion channel and the minimal K+ ion channel–related peptide 1, which represent the main ancillary single-transmembrane β-subunits associated with the α-subunits of KCNQ1 and KCNH2. Mutations in KCNE1 may cause either the dominant RW (LQT5) or, if present in homozygosity or compound heterozygosity, the recessive JLN.7 The cases of KCNE2 mutations associated with LQTS are few, and some of them represent acquired LQTS associated with specific drugs, almost all IKr blockers.7Among the sodium channel interacting proteins, the CAV3, SCN4B, and SNTA1 genes are regarded as additional LQTS genes (LQT9, LQT10, and LQT12).22–24 The AKAP9 is involved in the phosphorylation of KCNQ1, and its mutations have been described in LQT11.25 Two missense mutations in CACNA1C, encoding a voltage-gated calcium channel, are linked to Timothy syndrome (TS; LQT8), a rare and extremely malignant variant.26 Finally, in a large Chinese family, a heterozygous mutation was identified in the inwardly rectifying K+ channel subunit Kir3.4, encoded by KCNJ5. The variant was present in all the 9 affected family members and was absent in >500 ethnically matched controls, suggesting a role in the pathogenesis of the novel LQT13 variant.27On the other hand, the ANKB and KCNJ2 genes, often referred to as LQT4 and LQT7, are associated with complex clinical disorders in which the prolongation of the QT interval is modest and, in our opinion, should not be strictly considered as part of LQTS.7PrevalenceEven though it is customary, when dealing with any cardiac disease of genetic origin, to provide its prevalence, almost always what is presented is largely an educated guess. LQTS represents an exception. For too long, the prevalence of LQTS was assumed to be anywhere between 1/5000 and 1/20 000, without any supporting data. The first data-driven indication of the prevalence of LQTS was published in 2009, on the basis of the largest prospective study of neonatal electrocardiography ever performed.28 In 18 Italian maternity hospitals, an ECG was performed in 44 596 infants who were 15 to 25 days old; in this cohort, 0.07% had a QTc >470 ms, and 0.47% had a QTc between 451 and 470 ms. Molecular screening allowed the identification of a disease-causing mutation in 43% of the neonates with a QTc >470 ms and in 29% of those screened with a QTc between 461 and 470 ms. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% CI, 1:1583–1:4350).28 Considerations based on the number of infants with a QTc >450 ms who were not molecularly screened actually suggest that the prevalence of LQTS is close to 1:2000. This prevalence concerns only infants with an abnormally long QTc and cannot estimate the additional incidence of silent mutations carriers (individuals who carry a disease-causing mutation but who have a normal QT interval).Clinical PresentationThe clinical manifestations of LQTS have been described in detail too often to deserve additional repetitions here. The reader unfamiliar with LQTS can find these descriptions in previous publications.6,7,29 Here, we will mention only a few specific aspects that carry, in our opinion, special significance.The ventricular tachyarrhythmia that underlies the cardiac events of LQTS is Torsades-de-Pointes, a curious type of ventricular tachycardia that most of the time is self-limiting and produces transient syncope but that can also degenerate into ventricular fibrillation and cause cardiac arrest or sudden death.7 It would be extremely important to know what causes Torsades-de-Pointes to stop after a limited number of seconds or to continue, with devastating consequences, but we do not.The morphology of the T wave is often useful for the diagnosis, and the precordial leads are especially informative when they reveal biphasic or notched T waves.30 T-wave alternans in polarity or amplitude (Figure 1), when observed, is diagnostic as we proposed ≈40 years ago.31 T-wave alternans is a marker of major electric instability and identifies patients at particularly high risk; its presence in a patient already undergoing treatment should alert the physician to persistent high risk and warrants an immediate reassessment of therapy. Sinus pauses, unrelated to sinus arrhythmia, are an additional warning signal especially in patients with SCN5A mutations.7,32Download figureDownload PowerPointFigure 1. Examples of T-wave alternans from a 2-year-old long-QT syndrome patient with multiple episodes of cardiac arrest. Tracings are from a 24-hour Holter recording.Diagnosis and Genetic TestingTypical cases present no diagnostic difficulty for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of multiple variables besides clinical history and ECG. The diagnostic criteria for LQTS proposed in 19856 remain essentially valid for a quick assessment; however, a more quantitative approach to diagnosis became possible with the presentation of a diagnostic score in 1993 that became known as the Schwartz score, which was updated in 2006.33,34 The last update has just been made on the basis of the report on the diagnostic role of QT prolongation in the recovery phase of an exercise stress test35,36 (Table 2). The persistent use of the old scoring system by some investigators leads to an underestimation of the patients identified as probably affected and should be discontinued; a score of 3.5 points is sufficient for a high probability of LQTS.Table 2. LQTS Diagnostic Criteria of 1993 to 2011PointsElectrocardiographic findings*AQTc,† ms≥4803460–4792450–459 (men)1BQTc† 4th minute of recovery from exercise stress test ≥480 ms1CTorsades-de-Pointes‡2DT-wave alternans1ENotched T wave in 3 leads1FLow heart rate for age§0.5Clinical historyASyncope‡With stress2Without stress1BCongenital deafness0.5Family historyAFamily members with definite LQTS‖1BUnexplained sudden cardiac death younger than age 30 among immediate family members‖0.5LQTS indicates long-QT syndrome.*In absence of medications or disorders known to affect these electrocardiographic features.†QTc calculated by Bazett formula where QTc=QT/√RR.•Mutually exclusive.§Resting heart rate below the second percentile for age.‖The same family member cannot be counted in A and B.Score: ≤1 point: low probability of LQTS; 1.5–3 points: intermediate probability of LQTS; ≥5 points: high probability.Modified from Ref 36.The importance of a correct diagnosis has assumed a new dimension in the molecular era. A new responsibility for the clinician lies in the identification of the most logical candidates for molecular screening and relates to the availability and cost of genetic testing. The best example of this situation comes from a study by Taggart et al.37 In a group of 176 consecutive patients diagnosed as affected by LQTS and sent to the Mayo Clinic for management and genetic testing, they regarded 41% of them as unaffected, 32% as probably affected, and only 27% as definite cases of LQTS. Genetic testing confirmed the clinical assessment because disease-causing mutations were found in none of the unaffected, in 34% of the probably affected, and in 78% of the definitely affected. It follows that an exceedingly large number of patients incorrectly received the clinical diagnosis of LQTS by their own cardiologists.It is indeed in the selection of patients with a suspicion of LQTS that the Schwartz score becomes especially useful. As the score gives importance to the degree of QT prolongation, it should be obvious that it cannot help in the identification of the silent mutation carriers. The smart approach consists in the use of the Schwartz score for the selection of those patients who should undergo molecular screening (everyone with a score ≥3.0) and in the use of cascade screening38,39 for the identification of all affected family members, including the silent mutation carriers.Malignant SubtypesTwo well-defined LQTS variants carry an especially high risk and are difficult to manage, the JLN syndrome4,5 and the TS (LQT8).26The recessive JLN has the same cardiac phenotype observed in the RW type of LQTS, complicated by a more malignant course and by congenital deafness. The largest study of JLN, based on 187 patients, did show that ≈90% of the patients have cardiac events, that they become symptomatic much earlier than in the other major genetic subgroups of LQTS (Figure 2), and that they do not respond as well to traditional therapy.5 Of interest, the patients whose homozygous mutations involve KCNE1 instead of KCNQ1 are at lower risk.5Download figureDownload PowerPointFigure 2. Kaplan-Meier curves of event-free survival comparing Jervell and Lange-Nielsen syndrome (J-LN) patients with long-QT (LQT) syndrome type 1, LQT2, and LQT3 symptomatic patients (modified from Ref 5).The TS is an extremely rare variant characterized by marked QT prolongation associated with syndactyly and often presenting with 2:1 functional atrioventricular block and macroscopic T-wave alternans.26 Congenital heart diseases, intermittent hypoglycemia, cognitive abnormalities, and autism can also be present. Of the 17 children reported by Splawski et al,26 10 (59%) died at a mean age of 2.5 years.Genotype-Phenotype CorrelationThe clinical manifestations of LQTS may vary according to the different genetic background. The disease-causing gene is the main determinant of the clinical phenotype, but also the position of the mutation in the protein and the specific disease-causing mutation can contribute to clinical severity.Disease-Causing Gene and PhenotypeIn 2003, data on 647 patients of known genotype indicated that life-threatening events were lower among LQT1 patients, higher among LQT2 women than LQT2 men, and higher among LQT3 men than LQT3 women.40 The present study also provided the rather unexpected and important information that the number of silent mutation carriers, ie, individuals with a disease-causing mutation but with a normal QT interval, exceeds previous estimates and correlates with the specific genes. Indeed, silent mutation carriers represent 36% of LQT1, 19% of LQT2, and 10% of LQT3 patients.In 2001, Schwartz et al41 examined the possible relationship between genotype and conditions (triggers) associated with the events in 670 symptomatic patients with LQTS and known genotype. As predicted by the impairment in IKs current (essential for QT shortening during increase in heart rate), most of the events in LQT1 patients occurred during exercise or stress (Figure 3). A highly specific trigger for LQT1 is represented by swimming. Many of the events in LQT2 patients occurred during arousal, especially from auditory stimuli, such as sudden noises and telephone ringing, particularly when occurring at rest. Most of the events in LQT3 occurred while patients were asleep or at rest. LQT2 and LQT3 patients are at low risk for life-threatening arrhythmias during exercise because they have a well-preserved IKs current, allowing appropriate shortening of the QT interval whenever heart rate increases.Download figureDownload PowerPointFigure 3. Triggers for all lethal and nonlethal cardiac events in the 3 genotypes (modified from Ref 41).In a study of a uniquely large South African LQT1 founder population, we observed that faster basal heart rate and brisk autonomic responses are associated with a greater probability of being symptomatic, depending again on the gene-specific impairment of IKs.42,43 Relatively high values of baroreflex sensitivity imply an increased ability to change heart rate suddenly, and this could be harmful especially in LQT1 patients: sudden heart rate increases with impaired QT shortening favor the R-on-T phenomenon and initiation of ventricular tachycardia-fibrillation, whereas sudden pauses elicit early afterdepolarizations, which can trigger Torsades-de-Pointes.43 Even in the postpartum period, genotype is important because arrhythmic risk is higher for LQT2 than for LQT1 patients,44,45 probably because of sleep disruption and sudden awakening.Genotype-phenotype correlation exists also in rare and malignant forms of LQTS as shown by the fact that among JLN patients those with KCNE1 mutations exhibit a markedly less severe clinical course than the majority of patients who have mutations on KCNQ1.5Disease-Causing Mutations and PhenotypeIn 2002, Moss et al46 indicated that LQT2 patients with mutations in the pore region were at higher risk. In 2007, Moss et al47 demonstrated that in LQT1 patients both the transmembrane location of the mutation and their dominant-negative effect are independent risk factors for cardiac events. These studies were important because they called attention to the fact that not all mutations on the same gene produce a similar clinical phenotype and that they were the beginning of a growing number of intriguing revelations on the complexity of the genotype-phenotype correlation.Probably, the most striking example of mutation-specific behavior comes from KCNQ1-A341V, a hot-spot mutation characterized by unusual clinical severity demonstrated by 80% of the patients being symptomatic, with >30% experiencing cardiac arrest or sudden death (Figure 4).13,42 What is puzzling is that A341V is only a mildly dominant mutation producing a relatively modest loss of IKs. The implication is that our current understanding of biophysical cellular studies is still incomplete and fails to allow a direct translation into clinical reality.Download figureDownload PowerPointFigure 4. Unadjusted Kaplan-Meier estimate of the cumulative event-free survival (any first event) in the whole (non-South African - South African) A341V population plotted vs LQT1 non-A341V group. Any cardiac event, whichever occurred first, was considered from birth through 40 years of age and before β-blocker therapy. Numbers at risk are indicated (modified from Ref 13).Another example of mutation-specific behavior is represented by SCN5A-E1784K.48 This mutation is the most frequently described Brugada syndrome mutation, and it is also a relatively prevalent mutation among LQT3 patients. It can cause Brugada pattern, long QT, sinus node dysfunction, and life-threatening ventricular arrhythmias.48 The management of patients with this or other pleiotropic mutations49 should be careful, taking into account that their genetic background could favor different clinical manifestations; their management should be on the basis of the pattern manifested by multiple ECG recordings. However, even if the patient shows a pure LQT3 phenotype among sodium channel blockers, it is wise to avoid flecainide that may induce a Brugada pattern,50 whereas mexiletine is not contraindicated. In the study of family members carrying the same mutation, physicians should be aware that they could show clinical signs of either LQTS or Brugada syndrome and should be treated accordingly.Modifier GenesThe relationship between genotype and clinical phenotype is not necessarily linear in inherited arrhythmias. For example, in LQTS a genetic mutation may exhibit incomplete penetrance.51 Similarly, certain mutations may have variable expressivity, conferring different risk of disease expression in related individuals. Reasonably, both these aspects are linked to genetic, environmental, or developmental factors that may modulate the disease onset or its clinical severity. The genetic factors involved in this modulation, referred to as modifiers or modifier genes, are distinct from the disease-causing mutation and are the object of intense research activity.Some common genetic variants of cardiac ion channel genes (single nucleotide polymorphisms) have detectable functional activity. These findings underlie the concept that single nucleotide polymorphisms may modulate the clinical severity of the primary mutation. By investigating a highly symptomatic LQTS proband and her relatives, Crotti et al52 provided the first evidence that the common polymorphism KCNH2-K897T (30% carrier frequency among whites) may modify the clinical expression of a latent LQT2 mutation.The most powerful resource for studying modifier genes is represented by founder populations, in which a disease allele segregates in families descending from a common ancestor.53,54 In an unusually large South African LQT1 founder population,42 we demonstrated that 2 common variants in NOS1AP, encoding a nitric oxide synthase adaptor protein, were significantly associated with occurrence of symptoms, with clinical severity and QT interval.55 Subsequently, the role of NOS1AP as a genetic modifier of LQTS has been confirmed in a large cohort of unrelated patients.56 This type of study exploiting the unique features of the founder populations is likely to provide the much needed information necessary to allow a more precise custom-made risk stratification for the individual carriers of LQTS-causing mutations.Notably, the concept of modifier genes and of modifier factors illustrates the limitations of the cellular models currently used in the assessment of a functional defect. These models allow the biophysical investigation of putative mutations in single ion channels, potentially with the coexpression of specific, a priori selected variants (eg, single nucleotide polymorphisms). However, these heterologous in vitro systems may not completely reproduce all the possible channel interactions, such as the complex system of in vivo myocardial cell. Recently, pluripotent stem cells were generated from dermal fibroblasts collected from LQTS patients.57–59 These cells were successfully differentiated into cardiac myocytes, exhibiting functional alterations typical of the disease. The use of induced pluripotent stem cells may represent a novel and appropriate model to better elucidate the clinical heterogeneity in LQTS.Current ManagementThe most significant information concerning therapy for LQTS still comes from a 1985 study,6 which included 233 symptomatic patients and demonstrated the dramatic change