Author + information
- Received October 26, 2009
- Revision received December 1, 2009
- Accepted December 7, 2009
- Published online June 8, 2010.
- Nynke Hofman, MSc*,
- Hanno L. Tan, MD, PhD†,
- Marielle Alders, PhD*,
- Irene M. van Langen, MD, PhD* and
- Arthur A.M. Wilde, MD, PhD†,* ()
- ↵*Reprint request and correspondence:
Dr. Arthur A. M. Wilde, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Objectives The purpose of this study was to investigate the follow-up and treatment of the mutation-carrying relatives of a proband with an inherited arrhythmia syndrome.
Background The congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. After establishing the disease-causing deoxyribonucleic acid (DNA) mutation in probands, we actively conducted cascade screening to identify, most often asymptomatic, relatives who are also at risk of life-threatening arrhythmias.
Methods We retrospectively collected data from our cardiogenetics database and patient records and analyzed whether the identified carriers received prophylactic treatment.
Results From 1996 to 2008, 130 probands with a disease-causing mutation in one of the involved genes were identified, and 509 relatives tested positive for the disease-causing familial mutation. These subjects subsequently underwent cardiologic investigation (electrocardiography, exercise testing, Holter monitoring, ajmaline testing, echocardiography, where appropriate). After a mean follow-up of 69 ± 31 months (LQTS), 60 ± 19 months (CPVT), and 56 ± 21 months (BrS), treatment was initiated and ongoing in 65% (199 of 308), 71% (85 of 120), and 6% (5 of 81) of the relatives in the LQTS, CPVT, and BrS families, respectively. Eight carriers were lost to follow-up. Treatment included drug treatment (n = 249) or implantation of pacemakers (n = 26) or cardioverter-defibrillators (n = 14). All mutation carriers received lifestyle instructions and a list of drugs to be avoided.
Conclusions Cascade screening in families with LQTS, BrS, or CPVT, which was based on DNA mutation carrying and subsequent cardiologic investigation, resulted in immediate prophylactic treatment in a substantial proportion of carriers, although these proportions varied significantly between the different diseases.
Congenital long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. These arrhythmias are almost exclusively inherited as an autosomal dominant trait (1). In the past decade, the genetic basis of these arrhythmia syndromes has been unraveled more and more. Predictive testing using cascade screening in families with inherited arrhythmias is becoming more and more available as a result of this increasing yield of molecular genetic analysis. Predictive deoxyribonucleic acid (DNA) testing is warranted in these families because first-degree relatives have a 50% risk of carriership with a certain, although ill-defined, risk of lethal events and because most inherited arrhythmias can be treated successfully. Therefore, we believe that it is very important to inform affected families about the possibility of preventive treatment and risk stratification after predictive testing with the aim of preventing serious arrhythmias and sudden cardiac death. Due to the greatly varied expression and incomplete penetrance of these diseases, the decision to start treatment or not is not straightforward, particularly in asymptomatic patients. In our cardiogenetics department, we have >10 years of experience with these cases and, therefore, a long follow-up period. We studied what percentage of patients (carriers) are actually treated, the follow-up of all patients (treated or not), and the reasons why treatment was started or not. When a causative mutation is identified in the proband, cascade screening of the family is feasible, allowing pre-symptomatic treatment and appropriate lifestyle adjustments (2). Predictive genetic testing of relatives of a proband distinguishes carriers from noncarriers of the disease-causing mutation. For carriers, treatment and/or careful follow-up may be required. Noncarriers can be reassured that they are not predisposed to life-threatening arrhythmias and there is no risk of their offspring carrying the mutation.
LQTS and CPVT are heterogeneous. The major LQT types are caused by mutations in KCNQ1(LQT1), KCNH2(LQT2), and SCN5A(LQT3). Mutations in RYR2are responsible for the dominant form of CPVT, whereas CASQ2mutations cause the recessive form. Whether pre-symptomatic treatment is necessary depends on the disease. For both LQTS and CPVT, β-adrenoceptor blockers are the first choice of therapy (3). In LQTS patients, distinct genotype-phenotype correlations have been reported (4–6). Age at onset, symptom-related triggers, the ST-T segment morphology of the electrocardiogram, and the response to drugs are genotype specific. Timely treatment reduces the risk of cardiac events significantly, by 62% to 95% and by 74% in LQT1 and LQT2, respectively (7,8). In particular, in LQT1 β-blocker efficacy is very high, with failures almost exclusively due to noncompliance and/or the use of QT-prolonging drugs (7). The choice of treatment in carriers of LQT3 is more debated (β-blockers, prophylactic implantable cardioverter-defibrillator [ICD], left cardiac sympathetic denervation, or combinations thereof) (9,10). In BrS, pre-symptomatic testing is debated as well (11). In any case, all mutation carriers with LQTS or BrS should receive a list with drugs that must be avoided because they may precipitate lethal arrhythmias. Furthermore, all carriers should receive disease-related lifestyle modification instructions.
Taken together, treating physicians must contend with difficult therapeutic decisions, balancing the risks and benefits of the various treatment modalities.
The aim of this retrospective study was to evaluate whether pre-symptomatic genetic testing in the primary arrhythmia syndromes resulted in prophylactic treatment in mutation carriers. In addition, we evaluated which factors determine whether to initiate treatment.
In our multidisciplinary cardiogenetics outpatient clinic, genetic counseling and cascade screening for cardiogenetic diseases starts with the affected patient, the proband. Counseling sessions in probands and relatives combine the consultation of a cardiologist and a clinical geneticist or genetic counselor. Support from a psychosocial worker is routinely involved in predictive testing of minors. After the detection of a pathogenic mutation in the proband, the relatives are informed by letters written by the involved clinical geneticist or genetic counselor and distributed by the proband. When a relative expresses interest, he or she receives an appointment for genetic counseling. Once he or she decides to undergo direct predictive genetic testing, he or she gives written informed consent for DNA testing and related research for follow-up. Before the counseling session for predictive DNA testing, an electrocardiogram is obtained. The electrocardiographic findings can be discussed during the counseling session if the patient agrees, after discussing the advantages and disadvantages of predictive testing. The results of predictive DNA testing take about 4 weeks after counseling. In the meantime, treatment can be recommended if the results of the electrocardiogram (in LQTS) are obviously abnormal, combined with typical symptoms such as syncope.
The results of the DNA testing are given personally at the cardiogenetics outpatient clinic or by telephone, depending on the preference of the relative. Carriers of the familial mutation are referred for subsequent cardiological evaluation and regular follow-up, aiming to reduce sudden cardiac death. In addition to starting treatment with β-blockers or devices (pacemakers/ICDs), we counsel carriers, as a preventive measure, about lifestyle changes and the avoidance of particular drugs.
From 1996 until the end of 2007, 349 consecutive families were counseled because of LQTS, CPVT, or BrS. A pathogenic mutation was identified in 130 probands and active family screening (cascade screening) followed. Our study population consists of 509 consecutive relatives of 100 probands who tested positive for the familial mutation. Of the remaining 30 probands, the family members were not available, not tested, or tested negative.
Clinical data and follow-up
We retrospectively collected clinical data from our study cohort. These data included symptoms, the detailed family history of sudden cardiac death and syncope, and the use of drugs/devices. During the first visit, standard 12-lead electrocardiography in the supine position was performed. After the relatives were informed of the results of genetic testing, the carriers were referred for an additional clinical workup, treatment if necessary, and follow-up. Information about treatment and follow-up was collected from patient records or by contacting the treating physician. We determined the numbers of patients in whom treatment (drugs, usually a β-blocker, pacemaker, or ICD) was initiated, and compliance (defined as the patient reporting that therapy was continued as prescribed) with this treatment. We advise seeing all the (treated) patients at least once yearly and check the follow-up and compliance with treatment of all patients by the involved cardiologist. The start of follow-up (months) in treated patients was defined as the start of treatment; this was usually shortly after genetic testing. The start of follow-up in carriers without treatment was the moment when the results of pre-symptomatic testing were known. The follow-up period was completed at the end of 2008 or earlier in case the patient died.
In the LQTS relatives, the R-R and QT intervals were manually measured in lead V5, if possible, and the QT intervals were corrected using Bazett's formula.
Quantitative variables are presented as mean ± SD and categorical variables as percentages. Comparisons were performed using chi-square tests. The presented p values are 2 sided and considered significant when <0.05. Calculations were performed with SPSS version 15 software (SPSS, Inc., Chicago, Illinois).
Active cascade screening yielded 509 relatives who tested positive for the familial disease-causing mutation in KCNQ1, KCNH2, SCN5A, RYR2, or CASQ2. The mean age of the relatives was younger in relatives of LQTS and CPVT families (34 ± 22 years and 31 ± 22 years, respectively) than those of BrS families (48 ± 20 years) (Table 1).This difference reflects our advice to test children of LQTS and CPVT families at a younger age than those of BrS families because of an expected earlier onset, in general.
In LQTS, 199 of 308 mutation carriers were treated (65%), and their mean follow-up period was 69 months (range 6 to 150 months) (Table 2).The mean follow-up of the untreated mutation carriers was 54 months (range 18 to 121 months). The decision to initiate therapy was mainly based on whether symptoms were present (Table 3),QTc duration, and family history. There was a significant difference in QTc duration between treated and nontreated carriers (p < 0.0001) (Fig. 1).Still, in 59% (n = 108) of the LQT carriers with a QTc <460 ms, treatment was initiated. All subjects, including those with normal QTc, received a list of QT-prolonging drugs to avoid. Furthermore, we gave instructions about circumstances that may reduce serum potassium levels (diarrhea, vomiting) and may therefore increase the risk of arrhythmias.
In 163 subjects, β-blockers alone were started, 26 mutation carriers received a pacemaker, and 10 received an ICD (6 patients taking a β-blocker and 4 patients not taking a β-blocker). All pacemakers were implanted in members of 2 large (and probably related) families with LQT3, caused by the 1795insD mutation in SCN5A. This aberrant gene causes both an LQTS and a BrS phenotype, and pacemaker therapy has proven to be effective (12). Ten patients received an ICD because they had a severe phenotype. In 3 patients, this was caused by compound heterozygous mutations; 2 mutation carriers were symptomatic despite β-blocker treatment and 5 had a first-degree relative with sudden cardiac death. The latter 5 all carried an SCN5Amutation, 4 of whom carried p.Ile1768Val (a mutation that we consider particularly malignant). In LQTS type 1 mutation carriers older than 20 years of age who are asymptomatic and have QTc values <500 ms, treatment is not routinely initiated, based on results of risk stratification studies in large LQT1 cohorts (4,8,13). In our series, 47 of 77 LQT1 mutation carriers are treated. Of the remaining 30 subjects, 17 adult patients (older than 20 years of age) were not treated because they were asymptomatic and had a QTc <500 ms, whereas 2 declined treatment, and 10 were not treated because their phenotype was completely normal. Among these 10 subjects, 4 carried just 1 mutation and had a normal QTc duration, whereas the proband in this family had 2 mutations (compound heterozygous), and the other 6 were not treated because both probands had a completely normal phenotype and QTc prolongation was discovered coincidentally. One LQT1 carrier was lost to follow-up (Table 4).
Of 163 LQT2 patients, 121 were treated. Five patients died (see the following text). Forty-one carriers were not treated because of the following reasons: treatment declined (n = 3), not yet treated (n = 5), asymptomatic and normal QTc (n = 20), carrier of only 1 mutation, whereas the proband had 2 mutations (n = 4), age older than 60 years and asymptomatic (n = 9). One patient was lost to follow-up.
Of 68 LQT3 carriers, 31 were treated, 1 died, 4 were lost to follow-up, and 32 were untreated. Among them, 1 declined pacemaker implantation and 31 patients were untreated, based on an asymptomatic status, age, and a relatively normal electrocardiogram. Six subjects died during follow-up (Table 5).All but 1 were taking β-blockers. An autopsy was performed in none of them. One man died due of cancer at the age of 74 years. Another man died after an acute myocardial infarction complicated by ventricular fibrillation at the age of 59 years. Two others died within 2 years after they were identified as carriers. A woman died suddenly at the age of 52 years. She was treated with a β-blocker alone, although she had experienced cardiac arrest 8 years before, because she had significant cerebral impairment. A 65-year-old woman (LQT3) died at rest shortly after pacemaker implantation while taking β-blockers. Compliance with therapy was verified after the patients' death by interviewing close relatives.
Of 10 families, 120 relatives tested positive (64 from 1 family). The mean follow-up of treated CPVT carriers was 60 months (range 18 to 114 months). Eighty-five of them were treated with a β-blocker (71%), 1 received an ICD as well, and 1 carrier underwent a left cardiac sympathetic denervation (just like her sister, the proband) (14).
In general, treatment with a β-blocker was recommended for all carriers until an advanced age (about 70 years old). Eleven carriers were not treated because they carried a heterozygous CASQ2mutation, whereas the proband was homozygous. One other patient was considered too young to start treatment.
Four mutation carriers from a single family exhibited no ventricular ectopic beats during exercise testing. Whether the involved RYR2mutation in this particular family (c.14757-6C>T; c.14757-7T>A in intron 103) is disease causing is still being debated. Not all CPVT carriers followed the advice to take β-blockers; thus, 17 were untreated, including 5 persons aged older than 70 years. The mean follow-up of untreated CPVT carriers was 44 months (range 18 to 66 months). Two patients were lost to follow-up; no one died during follow-up.
Among 81 BrS carriers, 5 were treated (6.2%). Four of them received an ICD, but had no ICD shocks during follow-up. One mutation carrier had already received a pacemaker before he tested positive for the familial mutation because of conduction abnormalities. The mean follow-up duration was 56 months (range 30 to 78 months) in treated carriers, and 40 months (range 18 to 102 months) in untreated carriers. No one died during follow-up.
In our consecutive series, we found that immediate prophylactic treatment was started in a substantial proportion of carriers of a mutation causal to one of main arrhythmia syndromes (289 of 509, 57%). Initiation of therapy strongly depends of the type of disease. In LQTS and CPVT, 65% and 71%, respectively, of the mutation carriers were treated after a mean follow-up of almost 6 years; in BrS, only 6% were treated. Because the risks of and treatment options for arrhythmias in the different diseases are not completely comparable, the results are discussed separately.
Among our 308 LQTS patients (LQT1, n = 77; LQT2, n = 63, and LQT3, n = 68), 65% were treated after a mean follow-up of 69 months. Seven patients (2%) declined therapy, or discontinued taking a β-blocker daily. Compliance with therapy and follow-up in this patient group, therefore, is close to 100%.
Once treatment is started and evaluated, patients attend the outpatient clinic of the cardiologist once or twice yearly. In LQT1 patients, symptoms usually develop during physical activity (4,15), especially swimming (4,16). Because the LQT1 phenotype manifests at a young age, children are often treated well before they are 5 years old. The risk of events is strongly dependent on QTc duration (4,5,17). Other recently investigated predictors of events are the location of the mutation in the LQT1-associated gene (KCNQ1) and the biophysical effects of the mutation: patients with transmembrane mutations have longer QTc durations than patients with mutations in the C-terminus location, whereas dominant-negative mutations are associated with more events compared with those that cause haploinsufficiency (8). It is important to note that some specific mutations seem to have a significant malignant outcome (18).
In LQT2, there is more evidence of a first event at a later age than LQT1 (i.e., from puberty onward) (4,5). In addition to treatment with a β-blocker and the avoidance of QT-prolonging drugs, we advise LQT2 carriers actively change some lifestyle elements, such as the avoidance of sudden loud noises (e.g., ringtones and alarm clocks), because sudden auditory sensations often trigger arrhythmias in LQT2 (16). Female LQT2 carriers who desire to become pregnant receive extra monitoring after delivery because they have an increased risk of extra QTc prolongation shortly after delivery, possibly because of the combined effects of hormonal imbalance, stress, and fatigue (19–21).
LQT3 carriers show a large variation in phenotype. However, almost 50% of studied subjects (n = 30) in our series carry the 1795insD mutation in SCN5A. They exhibit a high incidence of nocturnal sudden death, bradycardia-dependent QT prolongation, intrinsic sinus node dysfunction, and generalized conduction abnormalities. Pacemaker implantation, in this large family with the 1795insD mutation, was shown to be effective in preventing sudden death (12).
In general, the management of LQT3 patients is complex. Although treatment with β-blockers lowers the heart rate, it has been observed that QTc duration in LQT3 patients increases even more at low heart rates (e.g., during the night), suggesting a higher risk of life-threatening arrhythmias. However, there is no clear evidence that β-blockers are contraindicated in LQT3 patients, and, unless patients had become symptomatic in the first year of life, they seem to be beneficial (10). Thorough examination (Holter monitoring) is recommended before starting β-blocker therapy and should be repeated during therapy.
Six LQTS patients died during follow-up (Table 5). Four of them died suddenly and unexpectedly without explanation. There was no autopsy performed of these patients, so we cannot exclude that cardiovascular heart diseases or other causes contributed to their death. Still, it is of concern that 2 LQT2 patients died shortly after treatment was started (8 months, and 4 months before death, respectively) and 1 LQT3 patient died within 10 days despite β-blocker and AAI pacemaker therapy. Although difficult to accept, and realizing these numbers are too small for conclusions, one has to consider the possibility that β-blocker therapy contributed to their death. Repeated monitoring (electrocardiographic, Holter) shortly after initiation of treatment thus seems mandatory.
Our results show an important clinical implication of positive genetic testing in families with LQTS: of all patients with a QTc <460 ms, 59% (n = 108) were treated after cardiologic investigation. These patients probably would have been missed if just electrocardiography was performed without genetic testing. In addition to that, as mentioned before, all LQT carriers receive lifestyle instructions and a list of QT-prolonging drugs to be avoided (7).
Seventy-three percent of the carriers of the familial CPVT mutation are treated (successfully). CPVT is characterized by exercise-induced or acute adrenergic stress–induced polymorphic ventricular arrhythmias, often causing syncope; a normal baseline electrocardiogram; the absence of structural cardiac abnormalities; and a high mortality rate (22–24). Genetic testing is important because the disease penetrance is not 100%, which suggests that a normal exercise test does not exclude carriership automatically. Symptoms usually develop during childhood or adolescence. In a substantial portion of cases, cardiac arrest is the first manifestation of the disease (23). Because the onset of the disease already manifests at a young age, we advise our families to test their children at an early age. As a principle, all carriers are treated with a β-blocker. Although β-blockers do not seem to abolish exercise-induced ventricular ectopy completely, they do protect against serious arrhythmias in most patients. In 1 patient (a sister of the proband), significant arrhythmias continued despite β-blocker therapy; she successfully underwent left cardiac sympathetic denervation (13). One patient received an ICD because of psychosocial distress caused by mutation carriership.
New treatments for CPVT are being considered. Because preliminary evidence suggests that flecainide might be successful (25), we are starting a study in a larger group of patients. In general, we advise all carriers to avoid intensive sports and exercise.
Of our 81 BrS mutation carriers, 5 were treated with an ICD or pacemaker. Four patients received an ICD because they had syncope (n = 2) or expressed an explicit preference for an ICD after extensive counseling (n = 2). All 4 had a first-degree relative who had had a sudden unexplained death. All patients who are tested positive for BrS receive a list of drugs to avoid (26). Moreover, they are advised to use antipyretic drugs during fever because a substantial proportion of BrS patients exhibit more severe electrocardiographic abnormalities and an increased risk of symptoms during fever (27). Accordingly, we advise all patients to visit the hospital during at least 1 fever episode to establish whether their electrocardiographic abnormalities worsen with fever. The age at which symptoms first occur is consistently during approximately the fourth decade of life in all studies, with no definite explanation for this observation. All carriers see a cardiologist once yearly for evaluation. Although symptomatic children were described rarely, recently more and more evidence is appearing about abnormal electrocardiograms in children with or without symptoms (28). In general, asymptomatic carriers with a normal baseline electrocardiogram seem to have a low risk of arrhythmias, although this is debated. In addition to treatment with an ICD, quinidine therapy is used in some patients. A registry assessing the effectiveness of quinidine has recently been suggested (29).
Taken together, the results of this study show quite a high number of disease carriers of LQTS and CPVT in which treatment is initiated shortly after confirmation of mutation carriership. Although it is impossible to quantify the benefit of this approach, it is safe to state that life-threatening arrhythmias are probably averted. In BrS, this assumption is less obvious because none of the BrS patients had serious arrhythmias during follow-up and none of the 4 with ICDs has had an appropriate shock.
Indeed, the follow-up of BrS carriers is possibly the most difficult part of the study population because the treatment options are limited and extreme (“wait and see” policy versus implanting an ICD). The large differences between the phenotypes of the Brugada probands and relatives are still unexplained, mainly due to the still-limited knowledge of the genetic causes of BrS.
Active cascade screening for disease carriership of relatives of LQTS, CPVT, or BrS probands leads to immediate prophylactic treatment in a substantial proportion of disease carriers. In LQTS and CPVT, 65% and 71%, respectively, of the carriers are treated. In BrS, only 6% of the mutation carriers are treated. These differences reflect differences in treatment options and variations in disease expression and penetrance. A large number of carriers are treated pre-symptomatically; these patients would have been missed without genetic testing. These and other data point to the need to identify all affected family members, independently of their QTc or symptoms, to prevent deaths. All LQTS and BrS carriers should receive a list of drugs to be avoided. All LQT1, LQT2, BrS, and CPVT carriers should receive lifestyle modification instructions.
Dr. Tan was supported by the Netherlands Organization for Scientific Research(NWO, ZonMW-Vici 918.86.616). Dr. Wilde's research program is supported by ICIN project 27 and a Leducq programgrant CVD05“Alliance Against Sudden Cardiac Death.”
- Abbreviations and Acronyms
- Brugada syndrome
- catecholaminergic polymorphic ventricular tachycardia
- deoxyribonucleic acid
- implantable cardioverter-defibrillator
- long QT syndrome
- Received October 26, 2009.
- Revision received December 1, 2009.
- Accepted December 7, 2009.
- American College of Cardiology Foundation
- Wilde A.A.,
- Bezzina C.R.
- Moss A.J.,
- Zareba W.,
- Hall W.J.,
- et al.
- Tan H.L.,
- Bardai A.,
- Shimizu W.,
- et al.
- Vincent G.M.,
- Schwartz P.J.,
- Denjoy I.,
- et al.
- Moss A.J.,
- Shimizu W.,
- Wilde A.A.,
- et al.
- Wilde A.A.,
- Jongbloed R.J.,
- Doevendans P.A.,
- et al.
- Choi G.,
- Kopplin L.J.,
- Tester D.J.,
- Will M.L.,
- Haglund C.M.,
- Ackerman M.J.
- Crotti L.,
- Spazzolini C.,
- Schwartz P.J.,
- et al.
- Seth R.,
- Moss A.J.,
- McNitt S.,
- et al.
- Rashba E.J.,
- Zareba W.,
- Moss A.J.,
- et al.
- Leenhardt A.,
- Lucet V.,
- Denjoy I.,
- Grau F.,
- Ngoc D.D.,
- Coumel P.
- Priori S.G.,
- Napolitano C.,
- Memmi M.,
- et al.
- Hayashi M.,
- Denjoy I.,
- Extramiana F.,
- et al.
- Probst V.,
- Denjoy I.,
- Meregalli P.G.,
- et al.