Ion Channel Diseases as a Cause of Sudden Cardiac Death in Young People

Aspects of their diagnosis, treatment, and pathogenesis

Background: Sudden cardiac death (SCD) is the death of an apparently healthy person within one hour of the onset of symptoms, or within 24 hours of last being seen alive and well—with no evidence of an extra-cardiac cause. In autopsied cases, SCD is defined as the natural unexpected death of unknown or cardiac cause. The reported incidence figures for SCD vary widely.

Methods: This review is based on clinical registry studies, meta-analyses, randomized controlled trials, systematic reviews, and current guidelines that were retrieved by a selective search in PubMed employing the key words “channelopathy,” “Brugada syndrome,” “long QT syndrome,” “catecholaminergic polymorphic ventricular tachycardia,” “short QT syndrome,” and “early repolarization.”

Results: Approximately 18% of cases of SCD in young persons are associated with cardiac channelopathy. The most common ion channel diseases affecting the heart are long QT syndrome and Brugada syndrome. The diagnosis is established by specific ECG abnormalities in the absence of structural heart disease. These can be unmasked by various maneuvers, e.g., the administration of sodium-channel blockers in Brugada syndrome. Imaging studies such as echocardiography, coronary angiography, and computed tomography are used to rule out structural heart disease and coronary artery disease. Long-term ECG and risk stratification scores can be useful aids to therapeutic decision-making. For some of these diseases, it is advisable for the patient to avoid particular triggers of ECG changes and cardiac arrhythmias in his or her everyday life. The near relatives of persons with congenital ion channel diseases should undergo clinical and genetic screening to protect them from SCD.

Conclusion: The affected families should be investigated systematically so that appropriate diagnoses and treatments can be established.

Sudden cardiac death (SCD) is defined as the death of an apparently healthy person within one hour of the onset of symptoms, or within 24 hours of last being seen alive and well. The definition of SCD also includes either a potentially life-threatening heart disease (previously known or discovered at autopsy), or no post-mortem evidence of an extra-cardiac cause.

The reported incidence rates for SCD vary (1) with age (children and infants: 1/100 000 person-years; 20– to 49-year-olds: 12/100 000 person-years; 50-to 60-year-olds: 50–60 /100 000 person-years, and age 80 and older: 200/100 000 person-years) and sex, with men generally being more frequently affected than women (2, 3, 4).

In the older population, the most common cause of SCD is coronary artery disease (CAD; 80%) with its associated acute complications, such as myocardial infarction and heart failure (5). Autopsy studies and clinical analyses of relatives have revealed as relatively common causes of SCD among young people hereditary cardiomyopathies (20%), ion channel diseases (18%) and myocarditis (5–7%) as well as rarely coronary anomalies (1–4% (6, 7). The European Society of Cardiology (ESC) Guideline for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death recommends to rule out extra-cardiac causes, such as drug abuse, electrolyte imbalances and endocrine disorders, when investigating the cause of SCD (8).

If a person with SCD receives timely and adequate cardiopulmonary resuscitation, SCD can be survived. After a survived episode of SCD, it is important to establish the cause of the event and to provide optimal drug treatment as well as primary prophylaxis in relatives, in addition to secondary prophylaxis with an implantable cardioverter defibrillator (ICD).

A recently published European guideline for the management of cardiomyopathies highlights the importance of genetic testing in patients and their relatives with suspected congenital cardiomyopathy (9). Affected individuals should be seen in specialized cardiogenetic centers for further diagnostic work-up. In patients with suspected ion channel disease as a possible cause of SCD, genetic testing is also advocated (8).

In this review, we focus on cardiac ion channel diseases, which are usually not associated with other structural heart diseases. In addition, we provide an overview of the pathogenesis of SCD and the available treatment options. The Deutsche Ärzteblatt has already published several articles on ion channel diseases, most recently in 2015 (10, 11, 12). Since 2015, various guidelines have been revised in the light of new research findings relevant to the diagnosis and treatment of ion channel diseases. Noteworthy in this context is a new guideline of the ESC published in 2022, as it contains considerably more information on the diagnosis and treatment of ion channel diseases than the preceding 2015 guideline (8, 13). The genetics of ion channel diseases has also been re-evaluated in several guidelines and consensus papers (14, 15, 16). Our article is based on current guidelines, studies and consensus papers related to ion channel diseases. We performed a selective search in the PubMed database, employing the key words “channelopathy,” “Brugada syndrome,” “long QT syndrome,” “catecholaminergic polymorphic ventricular tachycardia,” “short QT syndrome,” and “early repolarization.”

Cardiac ion channel diseases

Ion channel diseases comprise disorders of the function/expression of a wide variety of membrane proteins, resulting in changes in action potential properties that increase myocardial vulnerability which, in turn, can trigger cardiac arrhythmia. Cardiac ion channel diseases are often hereditary, but can be newly acquired in rare cases; they increase the risk of SCD in young people.

Long QT syndrome (LQTS) and Brugada syndrome (BrS) are the most common ion channel diseases, followed by catecholaminergic polymorphic ventricular tachycardia (CPVT) and the short QT syndrome (SQTS). Many cases of ion channel disease are only detected when members of a family are screened after one member of that family died of SCD. The current guideline recommends screening of first-degree relatives of patients with SCD and of relatives with symptoms, especially if the index case occurred in a person younger than age 50 years without clear cardiac cause (8).

Long QT syndrome

Epidemiology, diagnosis and symptoms

The prevalence of congenital or acquired long QT syndrome (LQTS) is 1:2000, with a predominance of the female sex. Medications (e.g., certain antibiotics and psychotropic drugs), electrolyte disorders (especially potassium and calcium balance) and cardiomyopathies (takotsubo cardiomyopathy) predispose to the development of LQTS (acquired LQTS).

Once secondary causes have been ruled out, certain criteria can be used as aids to the diagnosis of congenital LQTS (see ECG example in eFigure 1) which are summarized in eTable 1(8, 17).

eFigure 1

Graphic representation of the pathomechanisms of long QT syndrome and short QT syndrome.

eTable 1

Diagnostic criteria for congenital long QT syndrome (LQTS)*

eTable 2

Diagnostic criteria for congenital torsades de pointes*

Patients can present with diverse symptoms, including unexplained syncope, seizures, vertigo, atrial fibrillation, and, at worst, SCD as a consequence of ventricular tachyarrhythmia. The first cardiac event (syncope or cardiac arrest) occurs before the age of forty in 30% to 46% of patients with LQTS (LQTS1–3) (18). A number of different forms of LQTS have been described, based on the underlying genetic defect. An SCD can occur in a variety of situations, e.g., associated with predominantly physical stress in LQTS1, emotional stress (e.g., ringing of the alarm clock) in LQTS2, and in situations of rest (e.g., during sleep) in LQTS3.

An international expert group recommends genetic counseling and, in certain cases, molecular genetic testing of relatives if a pathogenic variant was detected (14). eFigure 1 shows a schematic representation of the pathomechanisms underlying LQTS as well as the various LQTS-associated genes.

Management

The current ESC guideline recommends basic measures for all patients with a confirmed diagnosis of LQTS, regardless of their symptoms (8). These include the avoidance of

• electrolyte disorders
• the use of QT-prolonging drugs (19), and of
• genotype-specific triggers.

Furthermore, the use of non-selective beta-blockers (nadolol or propranolol) is recommended in all patients with LQTS; however, this recommendation is weaker (class IIa) in the absence of symptoms without QTc prolongation. Asymptomatic patients with LQTS3 and persistent QTc prolongation despite beta-blocker therapy should be treated with mexiletine (class I recommendation) (8). A retrospective study found a lower risk of cardiac arrhythmias (3% versus 22%) in patients receiving mexiletine (20). Since different variants in the SCN5A gene respond differently to mexiletine, the QTc interval should be determined again after the first oral dose of mexiletine (effect defined as interval shortening by 40 ms).

Placement of an implantable cardioverter defibrillator (ICD) system is recommended as a secondary prophylaxis and/or in symptomatic patients with evidence of persistent QTc prolongation despite optimal drug therapy. Left cardiac sympathetic denervation (LCSD) is indicated if the QTc prolongation persists in symptomatic patients despite optimal drug treatment and/or in case of intolerance of or lack of adherence to drug treatment (8, 21). These measures are summarized in the Table.

Table

Summary of the treatment approaches for the various cardiac ion channel diseases based on the 2022 ESC guideline recommendations (8)

Brugada syndrome

Epidemiology, diagnosis and symptoms

The prevalence of Brugada syndrome (BrS) is 1:5000. Studies suggest that 20% of all SCDs in patients with macroscopically unremarkable hearts are attributable to BrS. Men between the ages of 30 and 45 are most commonly affected (23, 24, 25). BrS is thought to follow an autosomal dominant pattern of inheritance with age- and sex-dependent penetrance and expressivity (26, 27).

Details of the pathophysiology of BrS are shown in eFigure 2.

eFigure 2

Pathomechanism of Brugada syndrome

Characteristic symptoms include syncope, atrial fibrillation, sinus node dysfunction, ventricular fibrillation, and SCD (25, 28, 29). Typically, these symptoms occur during periods of increased parasympathetic tone (rest, sleep) (23) which are associated with an increased inhibition of sodium flux and consequently increased cardiac vulnerability, with ventricular tachycardia (36). Other triggers include the use of certain medications (e.g., class I antiarrhythmic drugs, psychotropic drugs) that have an effect on the voltage-dependent sodium flux (30). Especially in young children, fever can also be a trigger (31, 32, 33, 34).

BrS is diagnosed using electrocardiography. The diagnosis is established if a type 1 BrS ECG pattern is found (Figure 1). By using class I antiarrhythmic drugs (mainly ajmaline) and positioning the ECG electrodes in the second, third and fourth intercostal spaces, BrS is diagnosed with a sensitivity and specificity of 100% (35, 36). In the case of a type 2 BrS ECG pattern (saddleback ST-segment elevations in the right precordial leads V1–3) and suspected BrS, an ajmaline test may be indicated to unmask the condition.

Figure 1

Display of a type 1 BrS ECG, triggered by ajmaline test (administration of 1 mg/kg).

If the condition is suspected based on clinical features but the ECG is initially unremarkable, it may be possible to obtain a spontaneous type 1 ECG by shifting the right precordial leads (40) or by prolonged ECG monitoring (e1).

Here, it is important to rule out Brugada phenocopy which may occur with conditions such as electrolyte disorders, pericarditis, acute myocardial infarction, pulmonary embolism, or arrhythmogenic right ventricular cardiomyopathy (ARVC). Brugada phenocopy describes a type 1 Brugada-like ECG pattern in patients not diagnosed with BrS.

Fever and inflammatory situations seem to aggravate the BrS phenotype, potentially triggering, for example, ventricular tachyarrhythmia which may be mediated by an increased inhibition of sodium flux and inhibition of the expression of the SCN5A gene (e2) (eFigure 2). Molecular genetic testing of those affected and, if appropriate, their relatives is also recommended (15).

Management

According to current ESC guideline recommendations, all patients should avoid fever and, if they develop fever, should start antipyretic treatment immediately (8). Avoidance of substances potentially triggering BrS symptoms is an important part of primary prophylaxis (information regularly updated at [22]). In addition, it is recommended to avoid excessive alcohol consumption as well as cocaine and cannabis. This recommendation is based on case reports of an association between ventricular fibrillation and BrS observed with the consumption of these substances.

The secondary prophylaxis in BrS patients who survived SCD should include the implantation of an ICD system due to the fact that the 10-year risk of recurrence of ventricular tachyarrhythmia is 48% (e3, e4). In the case of an electrical storm, characterized by a minimum of 3 episodes of ventricular tachyarrhythmia within 24 hours and/or recurrent ICD shocks triggered by ventricular fibrillation, acute treatment with isoproterenol and/or hydroquinidine is recommended. Another treatment option to consider is epicardial ablation of the right ventricular epicardium (e5, e6), a procedure which can result in permanent normalization of the ECG (13, e7).

ICD implantation is recommended in BrS patients with arrhythmogenic syncope (8, 13).

The risk of sudden death is lower in asymptomatic patients (<0.5% per year)(e8). In these cases, ICD implantation is not recommended because of the risk of ICD system-specific complications (inappropriate shocks [18%], lead dysfunction [5%] [e9])). Ultimately, ICD implantation is also an option for asymptomatic patients in special and selected cases, based on an individual risk assessment (e10, e11, e12).

As a general rule, asymptomatic patients should be included in a monitoring program in a specialist cardiology setting (e13).

Catecholaminergic polymorphic ventricular tachycardia

Epidemiology, diagnosis and symptoms

The prevalence of catecholaminergic polymorphic ventricular tachycardia (CPVT) is approximately 1:10 000. Resting ECG recordings of these patients are usually unremarkable and tend show a lower resting heart rate (e14). In these patients, exercise ECG is the key diagnostic test as it triggers the characteristic, bidirectional or polymorphic ventricular tachycardia that confirms the diagnosis (Figure 2) (e15, e16). If bidirectional or polymorphic ventricular tachycardia occurs during exercise stress testing, the specificity for the diagnosis of CPVT is 97% and the sensitivity 50% (e17, e18). The diagnosis can also be establish by identifying a pathogenic mutation in genes associated with CPVT. If an exercise ECG is unsuccessful, an epinephrine or isoproterenol test can be performed (specificity 98%, sensitivity 28%) (e19).

Figure 2

Detection of bidirectional ventricular tachycardia during exercise stress testing in a patient with catecholaminergic polymorphic ventricular tachycardia.

Affected individuals can remain asymptomatic throughout life. A syncope triggered by emotional and/or physical stress is a typical symptom of CPVT.

Management

According to current ESC guideline recommendations, affected individuals should refrain from competitive sports. Treatment with non-selective beta blockers (nadolol or propranolol) is recommended irrespective of symptoms (8) (Table). An observational study including 216 patients found that 13% of patients experienced ventricular tachycardia despite treatment with beta blockers during the follow-up period of 9.4 years. In these cases, selective beta blockers were was associated with a 6-fold increased risk of ventricular tachycardia compared to non-selective beta blockers. If episodes of arrhythmogenic syncope or ventricular tachycardia continue to recur despite beta blocker treatment, pharmacotherapy with flecainide is indicated for these patient (e20).

After a survived SCD, an ICD should be implanted for secondary prophylaxis. ICD implantation is also recommended for symptomatic patients with syncope despite optimal pharmacotherapy (e18). Patients who do not tolerate the medication or experience persistent symptoms can be referred for LCSD therapy (e21, e22, e23). In a study with a follow-up period of 4.8 years, a median of 2.2% of the included patients died despite pharmacotherapy (e24). Avoidance of triggers and the use of non-selective beta blockers is also recommended for asymptomatic patients; apart from this, there are no further recommendations.

Early repolarization syndrome

Epidemiology, diagnosis and symptoms

Early repolarization syndrome (ERS) is a very common and usually benign condition with prevalence rates ranging from 5.8% to 23.9% in the total population and from 10% to 90% among athletes (e25, e26, e27, e28, e29). The high prevalence in athletes can be attributed to a high vagal tone. The prevalence of malignant ERS ranges between 8% and 44%. In experimental studies, ERS was associated with an increased vulnerability for cardiac arrhythmias (e30). In 2008, the risk of SCD associated with ERS was systematically investigated and demonstrated for the first time (e31). During a follow-up period of 61 ± 50 months, 41% of affected patients experienced recurrent episodes of ventricular tachycardia or suffered SCD. In another cohort of 630 subjects with ERS, 9.7% of the subjects died due to SCD during the 31-year follow-up period (e27). In most cases, ERS is associated with J-point elevation of more than 0.1 mV in two contiguous inferior and/or lateral leads (Figure 3). The diagnosis of ERS is established when other causes of SCD have been excluded. It is assumed that ERS is related to BrS (e28, e31). Patients with ERS are at an increased risk of ventricular tachycardia, but episodes of ventricular tachycardia are rare (e31, e32). Unfortunately, there are no data available that would allow risk stratification in ERS. The underlying genetic cause of early repolarization is still not fully understood (e33).

Figure 3

ECG of a patient with early repolarization syndrome in our hospital. Detection of J-point elevation >0.1 mV in at least two contiguous inferior leads

Management

The current ERS guideline recommends ICD implantation after survived SCD in patients with ERS for secondary prophylaxis (8) (see Table). The recommendation for patients with a family history of SCD in young people is to undergo clinical evaluations at close intervals and, if necessary, implantation of an event recorder. Isoproterenol and hydroquinidine can be used to treat an episode of electrical storm (≥ 3 appropriate episodes of ventricular tachycardia within 24 hours) (e34, e35).

Short QT syndrom

Epidemiology, diagnosis and symptoms

Almost 200 individuals worldwide have been diagnosed with idiopathic short QT syndrome (SQTS) since the condition was first described in 2000 (e36, e37). Given the lack of data, it is not possible to estimate the prevalence of SQTS. Symptomatic patients suffer from palpitations, syncope, presyncope, atrial fibrillation, bradycardia, and sick sinus syndrome (e38). The diagnosis of SQTS can be established based on a short QTc interval of ≤ 320 ms alone (Figure 4). SQTS can also be diagnosed based on QTc ≤ 360 ms in combination with arrhythmogenic syncope, a positive family history for SQTS, and/or a positive family history for SCD in young individuals, survived SCD, or detection of a pathogenic mutation.

Figure 4

ECG of a 23-year-old patient in our hospital, 25 mm/s, with short QT syndrome.

According to the Gollob criteria, a QTc up to 370 ms does not rule out SQTS (e39), eKasten. Apart from the congenital variant, electrolyte disorders or certain medications can also shorten the QTc interval, similar to LQTS (e40, e41). Secondary causes, such as primary carnitine deficiency, also lead to a shortened QTc interval.

The diagnosis could be confirmed by a lack of shortening of the QTc interval during exercise ECG testing, pointing to non-adaptation of the QTc interval. eFigure 1 shows the nine different genes associated with SQTS (16, e42). (16, e42).

Management

According to the current ESC guideline, ICD implantation for secondary prophylaxis is indicated in survivors of SCD (8). Asymptomatic affected individuals should be seen in a specialized outpatient clinic. The currently available data on the pharmacotherapy of SQTS are very limited. However, a retrospective study with 15 patients showed that hydroquinidine appears to reduce the risk of ventricular tachycardia (e43). Given the lack of data, the ESC guideline does not strongly recommend the use of hydroquinidine in patients with SQTS (class IIb).

Financial support

Mr. El-Battrawy thanks the Else Kröner-Fresenius Foundation (project number: 2022 EKES. 480), the Medical Faculty of the Ruhr University Bochum (project number: IF-034–22), and the German Heart Foundation for their financial support of the scientific projects.

Conflict of interest
The authors declare no conflict of interest.

Manuscript received on 21 July 2023; revised version accepted on 14 June 2024

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
PD Dr. med. Ibrahim El-Battrawy

Abteilung für Kardiologie und Rhythmologie, St. Josef-Hospital

Institut für Forschung und Lehre (IFL),

Abteilung für molekulare und experimentelle Kardiologie

Ruhr-Universität Bochum, Gudrunstraße 56, 44791 Bochum, Germany

Cite this as:
El-Battrawy I, Mügge A, Akin I, Nguyen HP, Milting H, Aweimer A: Ion channel diseases as a cause of sudden cardiac death in young people: aspects of their diagnosis, treatment, and pathogenesis.
Dtsch Arztebl Int 2024; 121: 665–72. DOI: 10.3238/arztebl.m2024.0130

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