Inherited arrhythmia syndromes and sudden cardiac death

• Inherited arrhythmia syndromes are genetic disorders in which a structurally normal or only mildly abnormal heart develops dangerous ventricular rhythms. They are an important cause of sudden cardiac death in young people and athletes.
• Brugada syndrome produces a characteristic electrocardiogram (ECG) pattern in the right chest leads and is dangerous at rest, with fever or with certain drugs.
• Catecholaminergic polymorphic ventricular tachycardia (CPVT) is set off by adrenaline: exertion or strong emotion triggers bidirectional or polymorphic ventricular tachycardia in an otherwise normal heart.
• Arrhythmogenic cardiomyopathy (ACM) is a genetic myopathy in which heart muscle is replaced by fibrous and fatty tissue, creating a substrate for ventricular arrhythmia and sudden death, often during sport.
• Finding one affected person normally means the whole family needs assessment, and anyone with a suspicious death needs a post-mortem and, where appropriate, a molecular autopsy.
• Management ranges from avoiding triggers, to drugs, to implantable cardioverter-defibrillators (ICDs) and catheter ablation, with decisions taken in a specialist, multidisciplinary team.

By the end of this page you should be able to:

1. Explain what inherited arrhythmia syndromes are and why they cause sudden cardiac death.
2. Recognise the typical presentation and ECG of Brugada syndrome, CPVT and ACM.
3. Outline how each syndrome is diagnosed and risk-stratified.
4. Describe the drug, device and ablation options for each syndrome.
5. Plan preparticipation screening for an athlete and cascade screening for a family.
6. Give sensible exercise advice for someone with each syndrome.

Inherited arrhythmia syndromes are a group of genetic disorders in which the heart's electrical system is unstable. They are sometimes called cardiac channelopathies because several of them arise from mutations in the genes that code for ion channels, but the group also includes the inherited cardiomyopathies that produce arrhythmia, such as ACM. These syndromes are unusual causes of death overall, but they are disproportionately important in children, young adults and athletes, because they can kill before they ever cause symptoms ^[3].

Many of the events occur during exercise or shortly afterwards. An episode of sudden cardiac death linked to sport is conventionally counted if it occurs during activity or within one hour of it ^[3]. In adults over 35 the usual underlying problem is coronary artery disease, but in the young the lead culprits are inherited cardiomyopathies and channelopathies ^[3]. In young athletes the incidence of sudden cardiac death has been reported as 0.3 to 0.5 per 100 000 in US high school athletes and 3.6 per 100 000 in Italian young athletes ^[3], and inherited arrhythmia syndromes may account for almost 35% of these events ^[3].

Because most of these conditions are inherited in an autosomal dominant pattern, diagnosing one person usually means that relatives are at risk too. Genetic testing is recommended as routine care for patients with genetic arrhythmia syndromes and for family members when a pathogenic variant has been found in the index patient ^[1].

Inherited arrhythmia syndromes and sudden cardiac death are, in practice, two overlapping ideas. An inherited arrhythmia syndrome is the genetic condition itself. Sudden cardiac death is the outcome it can produce: an unexpected death from a cardiac cause, usually from ventricular fibrillation, occurring within an hour of symptoms when witnessed or within 24 hours of last being seen alive in unwitnessed cases ^[3].

The syndromes covered here can be grouped in two ways.

1. Primary electrical disease with a structurally normal heart: Brugada syndrome, CPVT, long QT syndrome, short QT syndrome and idiopathic ventricular fibrillation. The pump looks normal on imaging; the fault is in the rhythm.
2. Arrhythmogenic cardiomyopathy: here the muscle itself is diseased, with fibrofatty replacement, so these are both a structural myopathy and an arrhythmogenic disease.

The 2022 European Society of Cardiology guideline on ventricular arrhythmias and sudden death prevention and the 2023 ESC Guidelines for the management of cardiomyopathies are the major European documents that define current practice, and a 2024 Heart Rhythm Society expert consensus on arrhythmias in the athlete covers sport, while the 2020 ESC Guidelines on sports cardiology and exercise address exercise advice. Where this page uses specific numbers or classes of recommendation, they come from open-access commentaries and reviews of those documents rather than from the guideline texts directly ^{[1] [4] [5]}.

• Brugada syndrome is rare, with population estimates ranging from about 1 in 2000 (roughly 0.5 per 1000 worldwide) to about 1 in 2500, and higher rates of 3.7 per 1000 in Southeast Asia and 17.7 per 1000 in Thailand ^{[2] [3] [6]}; some reviews quote 3 to 5 per 10 000 ^[6]. The diagnostic type 1 ECG pattern is found in roughly 0.5 per 1000 people worldwide ^[2]. Clinical disease is usually apparent in adults from about 40 years of age, and men are affected 8 to 10 times more often than women ^[2]. Brugada syndrome is said to be responsible for 4 to 12% of all sudden cardiac deaths and for about one fifth of sudden cardiac deaths in people with a structurally normal heart ^[2]. A family history of sudden cardiac death is found in roughly 26% of diagnosed patients ^[2].
• CPVT is also rare, quoted at about 1 in 10 000 ^[7], although one narrative review of exercise-related sudden death gives 1 in 20 000 ^[3]. It usually appears in childhood or adolescence and affects young males most often ^[3]. Without treatment the mortality is high, estimated at 30 to 50% by the age of 20 to 30 years ^[3].
• ACM has an estimated population frequency of 1 in 1000 to 1 in 5000 ^[4], with some reports giving lower estimates nearer 1 in 10 000; guideline documents reviewed for this topic continue to use the 1 in 1000 to 1 in 5000 range ^[4]. It is disproportionately common in young people and in athletes, in whom it is an important cause of sudden cardiac death ^[4].
• Sudden cardiac death in sport happens mainly in adults. The incidence in older athletes has been reported as 6.64 per 100 000 person-years ^[3], and men carry a risk roughly 2.6 to 4.3 times that of women ^[3].
• Genetic testing identifies a plausible cause in about 20 to 35% of sudden unexplained deaths in the young ^[3], which is why a molecular autopsy is so valuable.

These syndromes are genetic. Brugada syndrome is inherited in an autosomal dominant pattern with incomplete penetrance ^[2]. The most firmly associated gene is SCN5A, which encodes the alpha subunit of the cardiac sodium channel; pathogenic variants in it are found in about 15 to 30% of patients ^{[2] [6]}. More than 500 pathogenic variants have now been described across many ion channel genes ^[2].

CPVT is also dominantly inherited in most families. The ryanodine receptor gene RYR2 explains 60 to 70% of cases, and roughly 30% of RYR2 variants arise de novo rather than being inherited ^[3]. Rarer forms involve calsequestrin (CASQ2) and other calcium-handling genes ^[3].

ACM is usually familial too. Most cases involve desmosomal genes such as PKP2, DSP, DSC2, DSG2 and JUP, whose products hold cardiac muscle cells together; mutations weaken adhesion and lead to cell death and fibrofatty replacement ^[4].

Non-genetic triggers matter as much as the genes. Fever can unmask Brugada ECG changes and trigger arrhythmia. Drugs that affect ion channels, dehydration, exercise, emotional stress and catecholamines are central to CPVT and ACM. In ACM, exercise itself can drive disease progression, not just trigger an event, so it is both a trigger and a possible accelerator of the condition ^{[4] [5]}.

The ECG abnormality comes from a repolarisation or depolarisation disturbance in the right ventricular outflow tract, the muscular gateway from the right ventricle into the pulmonary artery. Reduced sodium current relative to the transient outward potassium current (Ito) means that the action potential dome is lost in some cells but not in their neighbours. That electrical gradient produces the coved ST elevation on the ECG and sets up the polymorphic ventricular tachycardia or ventricular fibrillation that causes sudden death. Fever increases this effect by further reducing sodium channel function.

Here the heart structure is normal and the problem is the release of calcium from inside the cardiac cell during stress. When adrenaline rises, abnormal ryanodine receptors leak calcium from the sarcoplasmic reticulum during electrical diastole. That extra calcium triggers delayed after-depolarisations, which fire premature beats and then bidirectional or polymorphic ventricular tachycardia. This is why the rhythm problem appears during exertion, fright or sudden wakefulness, and why a resting ECG is usually normal.

In ACM, genetic weakening of desmosomes causes cardiac myocytes to die and be replaced by fibrous and fatty tissue, usually starting in the right ventricle but often involving the left or both. The scarred myocardium conducts electrical impulses slowly and heterogeneously, so a stable rhythm can suddenly degenerate into ventricular tachycardia or fibrillation. This is also why ACM can present with heart failure late, long after the electrical problems begin.

Many people with Brugada syndrome are entirely well and are found only because of an ECG or a family history. The syndrome classically presents with:

• syncope, often at rest or during sleep, sometimes during fever
• documented polymorphic ventricular tachycardia or ventricular fibrillation
• aborted sudden cardiac death, which may be the first manifestation
• a family history of sudden death in a young relative

The syncope of Brugada syndrome is not provoked by ordinary exertion, which is a useful distinction from CPVT. Symptom onset is usually in adulthood, although cases are described at any age.

The hallmark is syncope or seizure-like activity induced by exertion or emotion. A child who collapses while running, climbing stairs or being startled, and who is well a few minutes later, should make you think of CPVT. The rests between episodes are normal, and the resting ECG is usually normal, which is part of the trap. Palpitations are described but patients often remember only the faint.

ACM has a long silent phase. When symptoms come they include:

• palpitations, often during exercise
• presyncope or syncope during or after exertion
• signs of right or biventricular heart failure in advanced disease
• sudden death, sometimes the first event

A young athlete who faints during training is the classic, alarming presentation. Symptoms often begin between the second and fourth decades.

• Brugada syndrome. The diagnostic type 1 pattern is a coved ST-segment elevation of more than 2 millimetres in at least two of the right precordial leads (V1 to V3), recorded in the second, third or fourth intercostal space (higher placements, especially the second or third, are used to reveal a concealed pattern), followed by a negative T wave. Types 2 and 3 patterns (saddle-shaped) are not diagnostic on their own. They become type 1 after a drug challenge with a sodium channel blocker such as ajmaline or flecainide ^[3]. Repeating ECGs matters, because the type 1 pattern comes and goes.
• CPVT. The resting ECG is often normal, occasionally showing sinus bradycardia or U waves. The diagnosis is made during monitored exercise, with increasing polymorphic and bidirectional ventricular ectopy as the heart rate rises, or with an isoprenaline infusion ^{[1] [3]}.
• ACM. ECG may show T wave inversion across the right precordial leads (V1 to V3), delayed activation (epsilon waves), low QRS voltages in the limb leads and ventricular ectopy of left bundle branch block morphology ^[4].

Transthoracic echocardiography and, increasingly, cardiac magnetic resonance (CMR) are central. In ACM, CMR tissue characterisation with late gadolinium enhancement is the key test for fibrofatty scarring and is essential for diagnosis and risk stratification ^{[4] [5]}.

Holter monitoring, event recorders and stress testing capture arrhythmia that is not present in clinic. For CPVT an exercise test is in effect the diagnostic test. In Brugada, 12-lead Holter and fever challenges may reveal a hidden type 1 pattern.

Genetic testing is recommended for patients with suspected or definite Brugada syndrome, CPVT, ACM, long QT syndrome, short QT syndrome and hypertrophic cardiomyopathy ^[1]. It is also recommended for first-degree relatives once a pathogenic variant is identified in the index patient ^[1]. Where a cause of death remains unexplained, targeted post-mortem genetic testing is recommended for the primary electrical diseases ^[1]. ^[5]

When a young person dies suddenly and unexpectedly, a complete medico-legal autopsy should be carried out ^[3]. If no cause is found the death is classified as sudden unexplained death, and a molecular autopsy, genetic testing of the deceased, may find a cause in 20 to 35% of cases ^[3]. That finding then drives the whole family's assessment.

The 2022 guideline tightened the diagnosis. A type 1 pattern on its own was enough under the 2015 document, but the newer guideline also requires clinical factors such as survived cardiac arrest, a positive family history of Brugada syndrome or a history of arrhythmic syncope ^[1]. A spontaneous type 1 ECG carries more weight than a drug-induced one, and in asymptomatic people with a spontaneous type 1 pattern an electrophysiology study may be considered for risk stratification ^[1].

Risk is highest after a cardiac arrest or in patients with spontaneous type 1 ECG plus syncope. Low-risk patients are those with a drug-induced pattern, no symptoms and no concerning family history. Because the pattern is intermittent, repeated ECGs at higher intercostal spaces and with Holter monitoring are often needed before a patient is labelled low risk.

Diagnosis rests on exercise-induced polymorphic or bidirectional ventricular tachycardia, isoprenaline-induced arrhythmia, a pathogenic genetic variant, or sudden cardiac death with a family history of CPVT ^[1]. There is no widely used quantitative score, which is an important limitation. Risk stratification therefore relies on documented arrhythmia on exercise testing, syncope and response to treatment.

Diagnosis uses the International Task Force criteria (1994, updated 2010), with subsequent expansion for left ventricular involvement: the Padua criteria in 2020 and the European Task Force consensus in 2024 ^[4]. These combine global and regional dysfunction on imaging, structural scar on CMR, late potentials on signal-averaged ECG, T wave and activation changes on ECG, arrhythmia and family history or genetic findings into definite, borderline and possible categories. Different guideline documents still disagree about definitions and about how to handle phenocopies and left-dominant disease, and there is no externally validated risk score yet ^[4].

For drug-risk versus device decisions, the 2022 guideline's approach to ACM is to consider ICD implantation in patients with moderate right or left ventricular dysfunction and either non-sustained or inducible sustained ventricular tachycardia ^[1].

Treat the person, not the label. Management combines avoidance of the specific trigger, drug therapy, possible device implantation and, for some, catheter ablation, within a multidisciplinary cardiogenetic service ^{[4] [5]}.

• Avoid triggers. Fever should be treated promptly with antipyretics. Drugs known to trigger arrhythmia (listed at brugadadrugs.org) should be avoided. An ECG is worth repeating during fever, because the type 1 pattern can appear for the first time.
• Quinidine is used in some patients, particularly those with recurrent arrhythmia or ICD shocks, because its effects on the potassium current can restore the action potential dome.
• ICD implantation is reserved for survivors of cardiac arrest or patients with arrhythmic, cardiogenic syncope, given that fragments of risk exist even in people who have never had symptoms. The exact indications remain a matter of clinical judgement and shared decision making.
• Catheter ablation is recommended more strongly than before, at class IIa level, for patients with Brugada syndrome and drug-refractory recurrent appropriate ICD shocks, targeting VF-triggering premature beats from the right ventricular outflow tract and the epicardial substrate there ^[1].
• A dedicated narrative review concludes that recreational and low-intensity exercise is not contraindicated, with caution about situations that raise body temperature ^[3].

• Beta-blockers are the first treatment: non-selective agents, specifically nadolol or propranolol, are preferred by the 2022 guideline ^[1]. This preference is because they blunt the adrenergic drive that provokes the arrhythmia.
• Flecainide should be considered in addition to a beta-blocker in symptomatic patients who have polymorphic or bidirectional ventricular tachycardia on testing, persistent exertional premature beats, or recurrent syncope, regardless of whether a disease-causing mutation has been found ^[1].
• Left cardiac sympathetic denervation has had its recommendation upgraded in both CPVT and long QT syndrome; it is considered when drugs are not enough ^[1].
• ICD implantation is for survivors of cardiac arrest, for malignant arrhythmia despite drug therapy, or when drug treatment fails, bearing in mind that shocks can themselves be proarrhythmic in CPVT.
• Trigger avoidance means limiting extreme exertion and intense competition, especially in the untreated or partially treated patient, and addressing emotional stress where possible. Even after treatment, low intensity and moderate exercise is the sensible aim.

• Heart failure therapy follows the standard chronic heart failure regimen, titrated as usual.
• Antiarrhythmic drugs are used for symptom and arrhythmia control; drug choice is guided by the individual substrate and by left ventricular function.
• Catheter ablation is an important tool for recurrent symptomatic monomorphic ventricular tachycardia, often epicardial because the scar is subepicardial in ACM.
• ICD implantation is the main tool for preventing sudden death in ACM. Guidelines agree on ICD therapy for sustained ventricular tachycardia, ventricular fibrillation or aborted sudden cardiac death, and on ICD consideration for patients with impaired right or left ventricular function and significant ventricular arrhythmia, although the precise threshold differs between documents and there is no externally validated score yet ^[4].
• Exercise restriction is a treatment, not just advice. High-intensity and competitive sport can accelerate fibrofatty replacement and provokes arrhythmia, so they are generally avoided. A period of deconditioning and reassessment is usual.

The 2023 ESC cardiomyopathy guideline recommends at least 150 minutes per week of moderate-intensity exercise for healthy adults and for people with known cardiac disease, with an individualised risk assessment for everyone whose condition puts them at risk ^[5]. That assessment is guided by three principles: preventing life-threatening arrhythmia during exercise, managing symptoms so that sport is possible where it can be safe, and preventing sport-induced worsening of the arrhythmogenic condition ^[5]. For any inherited arrhythmia syndrome the practical rule is the same: most patients can be active at modest intensity under supervision, but competitive and sudden high-exertion sport should be restricted unless a specialist service clears it.

For ACM specifically, the restriction is firmer than for Brugada syndrome: the arrhythmic substrate is worsened by exercise. For CPVT, competitive sport is not recommended in anyone with an identified genetic predisposition, including those who are asymptomatic, because cardiac arrest can be the first manifestation ^[3].

• Sudden cardiac death is the complication that matters most, and it is often the first event.
• Syncope and injury from arrhythmic events, including road traffic or water accidents.
• Psychological burden: living with an ICD, activity restrictions and the effect on the family, plus the risk of inappropriate shocks.
• Inappropriate ICD therapy, including shocks triggered by supraventricular arrhythmia or device problems.
• Ablation complications: cardiac tamponade, heart block, vascular injury and recurrence.
• Drug side effects: quinidine gut intolerance; beta-blocker fatigue and slowing; flecainide proarrhythmia if protective beta-blockade is inadequate.
• In ACM: heart failure, progressive right or biventricular dysfunction, and the risk of arrhythmogenic storm from scar.

Prognosis has improved greatly with modern care, but it depends on the syndrome and on how the patient presents. Survivors of a cardiac arrest who receive an ICD generally do well. Patients diagnosed incidentally without symptoms carry a much lower event rate but still need ongoing review, because risk accumulates over decades and ablation of concealed or rare patterns still leaves the substrate.

CPVT in particular carries a sobering untreated outlook, with 30 to 50% mortality by young adulthood ^[3], but combined non-selective beta-blockade, flecainide and, in selected cases, left cardiac sympathetic denervation have transformed outcomes. ACM is a chronic condition: arrhythmia and heart failure worsen with time and with continuing exertion, which is why treatment, surveillance and sensible restriction together determine outcome.

The honest uncertainty is this: for all three syndromes there is no simple, validated "treat or not" score for the patient with a concealed pattern. Decisions are therefore made in specialist centres, reviewed over time, and shared with the patient.

The ESC, the American Heart Association and the American College of Cardiology all recommend preparticipation cardiac screening for young athletes, with particular attention to identifying high-risk individuals ^[3]. Practical points:

• History is the backbone: exercise-related syncope, palpitations, chest pain, unexplained breathlessness, or a family history of sudden death in a young relative.
• Examination for murmurs, syndromic features and Marfan-type findings.
• ECG, which is cheap, quick and non-invasive but requires someone trained in athlete-specific interpretation, because training changes the normal pattern ^[3].
• Further testing, with echocardiography, stress testing and CMR, is triggered by abnormal findings. An ECG abnormality in an athlete always deserves explanation before clearance.

Relatives of an affected person, and of a young sudden-death victim, need assessment even if they feel well:

• three- to four-generation pedigree ^[4]
• detailed personal and family history
• ECG, echocardiogram, ambulatory rhythm monitoring and, where appropriate, CMR and an exercise test
• genetic testing, cascading from the index patient's confirmed pathogenic variant ^{[1] [4]}

During that screening, the clinician should remember that the resting ECG and even the resting echocardiogram can be normal in CPVT and in Brugada syndrome between events. A normal test never settles the question on its own.

Carrying a pathogenic variant is not the same as having disease. Relatives who carry a Brugada or CPVT variant but have a normal ECG and no symptoms need periodic review, fever precautions and sensible exercise advice, with treatment started at the first sign of electrical or clinical change. Relatives who do not carry the family's variant can usually be discharged from cardiac follow-up.

Public access defibrillators, basic life support training for coaches and teachers, and a written response plan at every sports venue are the simple measures that save lives in the gap before a diagnosis is ever made ^{[1] [3]}.

Brugada syndrome can present in children, particularly with fever. CPVT often debuts in childhood. ACM is unusual before adolescence. Screening is the same as for adults, with paediatric expertise, and genetic diagnosis opens the door to family-wide protection ^[3].

Brugada syndrome can worsen in pregnancy or feverish illness. Drugs commonly used in labour and in caesarean section need checking against the Brugada drug list. ICD therapy continues to apply. Beta-blocker therapy for arrhythmic indications can usually be continued ^[5]. All significant decisions should be taken by a multidisciplinary team including cardiology and obstetrics.

Late presentation is well described in Brugada syndrome and in ACM, where left ventricular involvement and heart failure may only become obvious with time. Comorbidity and competing causes of rhythm disturbance become important; not every ventricular ectopic in an older person is one of these syndromes.

A careful history and a 12-lead ECG are the tools that matter most. Where CMR, genetic testing and devices are unavailable:

• treat fever promptly in anyone with a Brugada pattern
• give non-selective beta-blockade empirically for a compatible CPVT phenotype
• use exercise and simple Holter monitoring to confirm CPVT
• avoid recommending competitive sport for a probable ACM until the diagnosis is clarified
• refer early to any centre with device and ablation capability
• keep family screening clinical when genetic testing is not available, remembering that not every relative with a normal ECG is truly low risk

• Inherited arrhythmia syndromes kill by sudden ventricular fibrillation; syncope or sudden death may be the first manifestation.
• Brugada syndrome is a night, rest and fever condition, with a coved ST elevation of more than 2 millimetres in the right precordial leads, provoked by sodium channel blockers.
• CPVT is an adrenaline condition: structurally normal heart, normal resting ECG, exercise-induced bidirectional or polymorphic ventricular tachycardia, treated first with non-selective beta-blockers (nadolol or propranolol).
• In CPVT, flecainide is added for persistent exertional premature beats, polymorphic or bidirectional tachycardia, or recurrent syncope. ^[1]
• ACM replaces muscle with fibrofatty scar; CMR tissue characterisation is the diagnostic pivot and exercise restriction is part of treatment.
• Genetic testing is recommended for the index patient and for relatives, and a molecular autopsy is recommended after a young sudden unexplained death.
• Athlete screening combines history, examination and ECG, with referral for any abnormality, because sport is the setting in which many of these syndromes first show themselves.
• ICDs protect survivors and high-risk patients; catheter ablation is valuable for Brugada syndrome with recurrent shocks and for ACM with recurrent ventricular tachycardia.
• Guidelines differ between European and North American documents in definitions, diagnostic criteria and device thresholds, so individual decisions belong in a specialist service.
• Sensible activity: low-to-moderate exercise is broadly acceptable with supervision, but competitive and sudden high-exertion sport is restricted in CPVT and ACM.

Inherited arrhythmia syndromes sit alongside, and overlap with, ventricular arrhythmias and sudden cardiac death, hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, short QT syndrome, cardiac MRI, ECG interpretation, cardiac physical examination and preparticipation screening of athletes. All of these warrant their own reading once the principles on this page are clear.