Inherited Cardiac Arrhythmias
Diagnosis, Treatment, and Prevention
Background: The incidence of sudden cardiac death in persons under age 40 is roughly 3 per 100 000 persons per year in Germany and North America. Many of these deaths are found to be due to hereditary heart diseases, often a primary structural heart disease associated with arrhythmia or else a primary arrhythmia syndrome in a structurally normal heart. Such diseases are usually of autosomal dominant inheritance, often affect otherwise healthy persons, and can generally be well treated if recognized early. Patients commonly have affected relatives who are still asymptomatic.
Methods: This review is based on articles up to May 2010 that were retrieved by a selective search of the Medline database via PubMed, with additional consideration of the relevant European and American guidelines and the German Law on Genetic Diagnosis.
Results and conclusion: Hereditary arrhythmia syndromes are now found in more than half of all initially unexplained cases of sudden cardiac death in young persons. Among such cases, the hereditary arrhythmia syndrome is primary in 70% and caused by an arrhythmogenic structural heart disease in 30%. In addition to autopsy findings, a thorough family history, relevant medical findings obtained during life (if available), the examination of relatives, and directed molecular testing where appropiate enabled establishing the diagnosis. Arrthymia syndromes that can cause sudden death are often detectable during life if physicians and the public are appropriately sensitized.
Hereditary arrhythmia syndromes are rare, but early diagnosis can markedly reduce the risk of sudden cardiac death. This is the more important because those affected are often young, otherwise healthy people. This article will give an overview of the current diagnostic and therapeutic options.
The aims of this article are to
- enable the reader to recognize signs and risk factors that should prompt suspicion of a congenital arrhythmia syndrome,
- describe what can be achieved with molecular genetic diagnostic tests,
- list the difficulties and limitations of interpreting genetic results,
- explain the treatment options, and
- list measures to prevent sudden cardiac death.
Among the hereditary arrhythmia syndromes a distinction is made between primary structural heart disease with increased arrhythmia risk and primary arrhythmia syndromes caused by dysfunction of the ion channels of the cardiac muscle (ion channel disease) (1–4). Although rare, because of their possibly fatal consequences it should not be left to cardiologists alone to recognize these diseases and the fact that they can be treated.
Among the most frequent structural changes that can be hereditary are hypertrophic obstructive and nonobstructive cardiomyopathy (H[O]CM), arrhythmogenic right-ventricular cardiomyopathy/dysplasia (ARVC/D), dilated cardiomyopathy (DCM), and noncompaction cardiomyopathy.
The most common ion channel diseases are long-QT syndrome (LQTS), catecholaminergic polymorphous ventricular tachycardia (CPVT), Brugada syndrome, and short-QT syndrome (SQTS). These diseases can become manifest at any age. The genetic structural cardiac diseases, too, sometimes remain undiagnosed until an advanced age. With each of these diseases, which usually follow an autosomal dominant pattern of inheritance, the pathological genotype is not always expressed in the phenotype. Even where the genotype is identical, the disease itself may vary within a family. Clinical findings are not always unambiguous. For example, in 513 genetically affected relatives in LQTS families, it was shown that although the average frequency-corrected QT interval (QTc) was slightly prolonged (454 ± 43 ms), half of the patients showed a normal QTc (5). In Brugada syndrome, in many patients a pathological ECG is visible only intermittently.
Typical first symptoms are palpitations, brief losses of consciousness with spontaneous recovery (fainting/syncope), or seizures caused by arrhythmias (arrhythmogenic seizures), especially if these are set off by specific triggers. The triggers may vary according to the disease. Typical of the most frequent forms of LQTS and CPVT is syncope during, for example, physical effort, swimming, or in psychological stress situations, after sudden noises (e.g., alarm clock), or after taking potentially repolarization-delaying medications (6–9).
In Brugada syndrome, arrhythmias tend to occur during sleep or with pyrexia (10). The primarily structural cardiac diseases with arrhythmia also often manifest for the first time not in the form of reduced tolerance of stress, but in arrhythmias.
Pathognomonic changes may be visible in the resting ECG (Figure 1 gif ppt). In most patients with LQTS, the frequency-corrected QT interval (QTc) is borderline to prolonged, or shows an abnormal T-wave morphology (e.g., notched, biphasic). In CVPT the resting ECG is typically normal; only in the stress ECG do frequent ventricular extrasystoles appear. In Brugada syndrome, a right bundle branch block-type deformation of the QRS complex in the form of a so-called Brugada type 1, 2, or 3 ECG may appear spontaneously or with pyrexia (Box 1 gif ppt). The cardiomyopathies (hypertrophic, arrhythmogenic right-ventricular, dilated, or noncompaction) sometimes manifest in the resting ECG with nonspecific repolarization disturbances; ARVC typically with T-wave inversions in leads V1 to V3 (after 14 years of age) and/or an epsilon potential. In LQTS, the high-grade arrhythmia underlying the symptoms is usually a specific polymorphous ventricular tachycardia (of the torsade de pointes type in which the QRS complexes seem to spiral around the isoelectric line); in Brugada syndrome it is a polymorphous ventricular tachycardia. In CPVT a bidirectional tachycardia, showing alternating QRS polarity, is typically causative of the symptoms, while in ARVC it is usually a monomorphous left bundle branch block-type ventricular tachycardia. There are no specific forms of ventricular tachycardia in the other cardiomyopathies. All the arrhythmias described here are often self-limiting, but can develop into ventricular fibrillation.
In rare cases the arrhythmia syndrome is accompanied by other abnormalities, such as the autosomal recessive hereditary Jervell and Lange-Nielsen syndrome with congenital hearing impairment, or Andersen syndrome (LQTS7) with sporadic muscle weakness, low-set ears, syndactyly, and other morphological abnormalities.
Today it is assumed that about 90% of hypertrophic cardiomyopathies are inherited; in about 60% of cases a causative mutation in genes encoding sarcomere proteins is found. In about 40% of patients with ARVC a mutation is found in one of the genes for desmosomal proteins. In the case of LQTS and CPVT, in 60% to 70% of cases a mutation is found in the five genes that most often cause LQTS, which encode cardiac potassium or sodium channels; for CPVT it is the RYR2 gene, which encodes the calcium release channel in the cardiac sarcoplasmic reticulum. In dilated cardiomyopathy, a familial form of the disease is seen in about 30% of patients. In this case the hit rate for identifying a causative mutation is currently around 30%. In Brugada syndrome, a causative mutation in the SCN5A gene, which encodes the cardiac sodium channel, is detected in about 26% of cases (Box 1). In all of these diseases, failure to identify a mutation by no means rules out (familial) disease; in the end it is always a clinical diagnosis. Genetic diagnostic techniques do contribute greatly to confirming the diagnosis, however, and in some cases also to genotype-based therapies. They also allow targeted examination of relatives who could potentially be affected.
Initial diagnostic procedure
The initial diagnostic step is a 12-lead resting ECG, a stress ECG, a long-term ECG, and an echocardiographic examination. This should be followed by a thorough family history encompassing three generations. The patient should be asked explicitly about any cases of sudden death, incidents of syncope, or seizures. These noninvasive tests are often enough to allow a (suspected) diagnosis (Figure 1, Box 2 gif ppt).
Indications for further diagnostic procedures
Cases of sudden death at a young age among relatives, incidents of syncope, documented arrhythmias, or atypical epilepsy in the context of specific triggers should all prompt further investigation. A clinical evaluation is the first step towards determining the probability that a hereditary arrhythmia syndrome exists (Figures 1 and 2). If there is reason to suspect that it does, genetic testing should be carried out for confirmation. If a pathogenic mutation is documented in the patient, this information can be used for diagnostic or predictive genetic testing of relatives (2, 5).
Further clinical diagnostic procedures
If Brugada syndrome is suspected (Brugada type 2 or type 3 ECG), a 12-lead resting ECG in which the electrodes for leads V1 and V2 are placed one intercostal space higher can increase the sensitivity. A provocation test with ajmaline can unmask a hidden diagnostic Brugada type 1 ECG (10). In most of the diseases under discussion here, electrophysiological examination looking for whether ventricular tachycardia can be induced is of no confirmed documented use, but in individual cases it can be useful in showing up conduction disturbances. If a structural heart disease is suspected, magnetic resonance imaging can add information (Figure 2 gif ppt). The importance of genetic diagnostics varies between the different diseases. It is very useful to confirm a diagnosis of LQTS or CVPT, and can help in risk stratification in the familial cardiomyopathies (e.g., there is a higher risk when a mutation of the LMNA gene is present).
Genetic diagnostic testing
For all the (suspected) diagnoses described here, molecular genetic testing can be carried out. The genes most often involved, which are worth investigating and can at present be tested routinely, are listed in Box 1. Other genes, if suspected, can be tested on an individual case basis at specialist laboratories or as part of scientific projects (further information at www.ncbi.nlm.nih.gov/sites/GeneTests).
When the causative genotype is identified in a patient, there is an option to carry out diagnostic or predictive genetic testing in at-risk persons among the patient’s relatives. For autosomal-dominant inheritance, this means testing the first-degree relatives of the symptomatic person following a step-wise or “cascade” pattern; for autosomal-recessive inheritance (e.g., Jervell and Lange-Nielsen syndrome) the siblings of the symptomatic person may be tested first. Ruling out the presence of the familial mutation or the causative genotype can reassure an at-risk person and usually makes further clinical investigations unnecessary. If the familial risk constellation is demonstrated in relatives, the general preventive measures and, if appropriate, medical therapy are recommended (Table gif ppt). For both diagnostic and predictive genetic testing, the stipulations of the German Genetic Diagnostics Law must be observed.
Problems in interpreting test results
A “negative” search result for a mutation never rules out a well-founded clinical diagnosis. The sensitivity of the tests offered for routine investigation at present is around 26% to 70%. If a result is positive, its plausibility must still be tested, since it may be that the mutation identified is not the cause—or not the sole cause—of the disease (12).
Without a suspected diagnosis, there is no point in carrying out a general genetic test (“to screen for every known gene that is known to be associated with sudden cardiac death”). Such screening often finds variants or even mutations that were not causative of the disease in the particular case, and thus can easily result in a misdiagnosis, which in turn would lead to false worry, or a false sense of security, in other relatives.
Even where there is a very definite suspected diagnosis, sometime a finding cannot be correctly interpreted without genetic and clinical testing of relatives, especially if the mutation in question is hitherto unknown. This often happens. Moreover, in about 5% of cases there are two mutations present in one gene or different genes. In addition, the same mutation can result in different phenotypes even within one family (e.g., for the SCN5A mutations: LQTS 3, Brugada syndrome, cardiac conduction disease, atrial fibrillation, or DCM) (14, 15).
Another difficult situation in interpreting results is when a frequent genetic variant (polymorphism) is found that basically accords well with the phenotype but does not explain the severity of the disease. Sometimes it is not discovered until years later that a mutation believed to have caused the disease was actually an irrelevant polymorphism. For none of the diseases discussed here can a genetic test result predict whether a patient will develop symptoms or what the course of the disease will be. However, in most cases presymptomatic treatment and the avoidance of specific triggers can influence the course of the disease.
Psychosocial aspects of genetic testing
The psychosocial stress of being diagnosed with an inherited disease varies greatly. Patients who have already been suffering from symptoms for which no disease could be identified are often relieved to have a diagnosis and the targeted treatment that a diagnosis makes possible. This is particularly true of the ion channel diseases, which are not progressive, and especially the most frequent LQTS types 1 and 2, which are well treatable.
The asymptomatic relatives who hear of the diagnosis react very variously. Reactions range from positive dealing with a disease that basically is treatable to fear that is hard to make an impression on. Psychotherapeutic counseling is often difficult in these cases, since it is not a matter of persuading the patient that any symptoms he or she experiences are harmless. In addition, in some cases these patients have already lost a relative to this disease. In this situation there is certainly an urgent need for a suitably trained therapist. Children seem to have fewer problems with the disease and better coping strategies, unless they have already lost a close relative to the disease. The better children had the disease explained to them, and how they could influence its course themselves, the better they coped (16, 17). However, the case is often different with the primary structural diseases, which are progressive, and for which the utility of prophylactic treatment is not always unambiguous. Asymptomatic mutation carriers should refrain from taking part in intensive sports activities. In such cases the question of whether to carry out presymptomatic genetic testing should be considered particularly carefully. This does not always result in relief for unaffected relatives, as has often wrongly been assumed, but can lead to severe psychological stress for them, with feelings of guilt and sympathy with the affected family members.
German Genetic Diagnostics Law
The German law on genetic testing, the Genetic Diagnostics Law (Gendiagnostikgesetz, GenDG) came into effect on 1 February 2010. This law aims to “set the preconditions for genetic testing and to prevent disadvantage occurring on the basis of genetic qualities, in order to maintain in particular the statutory obligation to respect and protect human dignity and the right to informational self-determination” (§ 1 GenDG).
This law regulates, among other things, who may undertake the genetic counseling before and after genetic testing. The task of developing guidelines was passed to the Genetic Diagnostics Commission (Gendiagnostik-Kommission, GEKO). So far, genetic counseling in the context of genetic testing has been carried out predominantly by clinical geneticists or physicians with an additional specialization in clinical genetics. This was not clearly regulated, however, and there was a danger that, as genetic testing became more available, it would take place without proper explanation and counseling carried out by appropriately trained persons.
Thus, since 1 February 2010, only physicians are allowed to order diagnostic genetic tests, and genetic counseling should be offered when the result is known; for predictive genetic tests, counseling by a clinical geneticist (or alternatively a physician with an additional specialization in clinical genetics) must be offered before and after the test is carried out. From 1 February 2012, this genetic counseling will also be able to be carried out by appropriately qualified physicians as part of their work within their own specialty, once they have obtained a qualification in “specialty-related genetic counseling.” Aspects of genetic counseling that go beyond this will continue to be reserved for clinical geneticists or physicians with an additional specialization in clinical genetics. The responsible physician who has undertaken the counseling must document what was said in the counseling. Genetic counseling by a physician qualified for this task is not the same as patient information given in the course of obtaining informed consent, but goes far beyond this in terms of required content and the time required to be taken over it. (Sources: German Genetic Diagnostics Law of 31 July 2009 and GEKO Guideline on the Requirements for Qualification for and Content of Genetic Counseling according to § 23, section 2, no. 2a and § 23, section 2, no. 3 GenDG as formulated on 28 January 2011).
Treatment and prevention
The Table gives an overview of the preventive and therapeutic options, following the guidelines of the specialist medical societies of Europe and the USA. The details of the various treatments are not the main topic of this review article, and so the authors make no claim that the information in the table is complete. The decision to institute each therapeutic recommendation is to be made after careful consideration in each individual case. Most of the available data originate in register studies or case reports. Randomized studies are not available and probably never will be.
In all cases, the recommendations about a particular lifestyle are of central importance. There are concrete preventive measures to take to avoid specific triggers, and patients must be informed about these. Ideally this will result in the affected persons’ feeling that they can to some extent control the severity of their disease themselves. Generally recognized preventive measures for persons with asymptomatic carrier status are to avoid intensive physical activities, especially competitive ones, since these increase the risk that cardiac arrhythmias will occur and can have a negative influence on the disease course. Moderate physical activity is usually allowed and indeed desired (18). Specific, genotype-related preventive measures are:
- No competitive sports (valid for all arrhythmia syndromes)
- Don’t go swimming alone and don’t jump into cold water (especially LQTS1 and CPVT)
- Avoid sudden loud noises (LQTS2)
- Don’t take potentially QT-prolonging medications (see www.qtdrugs.org) (all forms of LQTS)
- Avoid medications that are contraindicated for Brugada syndrome (www.brugadadrugs.org).
Pyrexia is a risk factor for arrhythmias in both LQTS and Brugada syndrome, and the fever should be brought down early, e.g., with paracetamol. This should be comprehensively explained to the person affected. Affected persons should always be given an up-to-date list of the typical risk factors for their disease. Those whose work involves a great deal of physical strain or potential danger to themselves or others if they should suffer syncope should consider a change of occupation.
Pharmacotherapy with beta-blockers is well established for LQTS and CPVT and is predominantly recommended both for symptomatic mutation carriers (secondary prophylaxis) and asymptomatic mutation carriers (primary prophylaxis) (19–21). In addition to the therapeutic measures described, there is the therapeutic option of left cardiac denervation in patients with refractory LQTS or those with CPVT.
In patients with LQTS in whom ventricular tachycardia occurs despite beta-blocker therapy and despite their following instructions about preventive measures, implantation of a defibrillator should be considered (21). For carriers of an SCN5A mutation, treatment should be decided on case-by-case basis. For all persons affected by this mutation there are specific preventive measures. The usefulness of prophylactic pharmacotherapy is less clear here (Table). In the structural heart diseases, the therapeutic utility for the patient of the genetic test result is much more limited. In this case the result is to be seen merely as one stone in the mosaic and usually has little influence on management. An exception to this is a mutation of the LMNA gene, which would lead to a lower threshold in recommending placement of an implantable cardioverter defibrillator (ICD) (22, 23).
In DCM with complete bundle branch block and mild to moderate heart failure (NYHA class II and III) despite optimal pharmacotherapy, the current recommendation is for cardiac resynchronization therapy (CRT), with or without an ICD (“triple-chamber pacemaker” or “triple-chamber ICD”). In HCM with extensive symptoms with obstruction of the outflow tract, transcoronary ablation of septal hypertrophy (TASH) or surgical myectomy is often indicated. Patients with cardiomyopathy that remain refractory to treatment should be evaluated early enough with a view to a heart transplant. The prognosis of the diseases described here is usually good if they are recognized early enough and treated appropriately. This applies in particular to the primary arrhythmogenic diseases, in which life expectancy is not reduced in most cases so long as treatment is appropriate. In the structural forms of disease, the course is partly determined by the progression of the cardiac muscle changes, which can be very variable.
Long-term care shared between family physician, cardiologist, and specialist centers
Family physicians are required, if one of their patients under the age of 60 dies suddenly and from unknown causes, to press for an autopsy and the taking of a blood sample. Family physicians should be in a position, on the basis of a thorough family history, to identify affected persons from families obviously at risk for sudden cardiac death. When the family or individual history suggests the possibility of an inherited cardiac arrhythmia disorder, the initial diagnostic procedure becomes very important. The first suspicion must usually be voiced by the family practitioner or the cardiologist to whom he or she refers. Any further necessary diagnostic tests (special imaging techniques, event recorder, invasive diagnostics), including whether molecular genetic testing would be worthwhile, should be decided on in close collaboration with a specialist center. Treatment decisions, regular treatment monitoring, and risk stratification should also be carried out regularly in close collaboration between family physician, cardiologist, and a specialist center throughout the life of the patient. Because these diseases are rare, and there is therefore a lack of large studies, risk stratification should be guided by guidelines issued by the national and international cardiological societies together with review articles and—equally important in the case of rare diseases—case reports and case series. Treatment with an ICD, which may appear to both patient and physician to be safest for the patient, should always be weighed up very carefully. The patient’s quality of life can be greatly restricted by ICD-associated complications, which occur in up to 30% of ICD patients. In many cases, also, non-sustained ventricular tachycardia can lead to ICD shocks and thus in turn to catecholaminergically triggered tachycardia storms, especially in CPVT (24). It is extremely rare that implantation of an ICD is indicated merely on the basis of a genetic result. Because of the low prevalence of these diseases, in the long term major progress in treatment can only be made by collecting patients together in specialist centers and by international collaboration between such centers.
In future, gene sequencing will be faster and available more cheaply (e.g., next-generation sequencing), so that in theory even large numbers of genes can be investigated simultaneously. This will not make recommendations for therapy any easier, as already, with only targeted sequencing of individual genes, variants and mutations are often found whose clinical significance is unclear. Thus, careful evaluation of genetic test results is becoming increasingly complex. Progress for patients will only come with “wise use and even wiser interpretation” of genetic testing in these potentially deadly, but treatable diseases (25).
A considerable percentage of inherited cardiac arrhythmias that can lead to sudden cardiac death at a young age can be recognized and effectively treated so long as the warning signs in the individual and family history are picked up and an ECG is carried out. Family physicians, pediatricians, cardiologists, anesthetists, neurologists, forensic medical specialists, and pathologists all have key roles in identifying at-risk patients and families. If there is reason to suspect the presence of an inherited cardiac arrhythmia disease, long-term collaboration between family physician, cardiologist, and specialist center is important, so that together they can establish an individualized diagnosis, systematic investigation and counseling of the family, and treatment decisions and risk determination. Comprehensive counseling for affected families, rigorous evaluation at regular intervals of the cardiac risk, and continual adjustment of therapy all contribute to reducing the incidence of sudden cardiac death in these families.
Conflict of interest statement
Professor Kääb and Dr Beckmann received funding for the following research projects: ANR SCD Gene: 01 KU 0907, M4 Innovative Therapiestrategien für Herzrhythmusstörungen; Drug Safety: 01 EX 1021 E, NGFN Plus: 01 GS 0838.
Dr Pfeufer declares that he has no conflict of interest.
Manuscript submitted on 4 May 2011, revised version accepted on 4 July 2011.
Prof. Stefan Kääb
Medizinische Klinik und Poliklinik I, Klinikum der Universität München
Großhadern (LMU – Großhadern)
Marchioninistr. 15, 81377 München, Germany
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EURAC Institut Bozen: Dr. med. Dipl.-Biochem. Pfeufer
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