Inherited cardiac conditions and sudden cardiac death

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Inherited cardiomyopathies include hypertrophic, dilated and arrhythmogenic phenotypes; channelopathies include long-QT syndrome, Brugada syndrome and catecholaminergic polymorphic VT. Phenotype and genotype overlap, so evaluation is multidisciplinary.

After sudden arrhythmic death syndrome, the aim is not to assign a speculative label but to preserve samples, review expert pathology and systematically screen relatives. Findings must be communicated with psychological and reproductive support.

Key points

Think inherited disease with young sudden death, exertional syncope, unexplained seizure-like episodes, cardiomyopathy, characteristic ECG changes or multiple affected relatives.
Construct a three-generation pedigree and verify diagnoses/death circumstances where possible.
A normal resting ECG and echo do not exclude a channelopathy or early cardiomyopathy.
First-degree relatives after sudden unexplained death should receive clinical screening through an NHS inherited-cardiac-conditions service.
Genetic testing starts with an appropriately phenotyped affected proband or retained post-mortem DNA when possible, with pre- and post-test counselling.
A pathogenic or likely pathogenic variant can enable predictive cascade testing; a variant of uncertain significance must not be used alone for predictive diagnosis.
Risk-reduction advice is condition-specific: exercise, fever, medicines, electrolytes, pregnancy and ICD decisions cannot be generalised across all inherited conditions.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Inherited cardiomyopathies

Pathogenic variants affecting sarcomeres, cytoskeleton, desmosomes or nuclear structures can produce hypertrophic, dilated or arrhythmogenic phenotypes. Fibrosis and ventricular remodelling create both pump failure and arrhythmic risk.

Inherited channelopathies

Variants affecting cardiac ion channels or calcium-handling proteins alter depolarisation, repolarisation or excitation–contraction coupling despite an apparently structurally normal heart. Long-QT, Brugada and catecholaminergic polymorphic VT phenotypes may remain concealed between triggers.

Syndromic and multisystem genetic disease

Storage, mitochondrial and neuromuscular disorders may involve myocardium or conduction tissue alongside renal, neurological, skeletal or sensory features. Recognising the wider phenotype guides appropriate genetic evaluation.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Inherited molecular defect
An inherited molecular abnormality may alter a structural protein, ion current or cellular metabolic pathway, even when no causal variant is yet identifiable. Dominant inheritance is common, but inheritance pattern and expression vary between conditions and within families.
2
Phenotype emerges
Age, additional genetic factors and environmental exposure influence penetrance. Hypertrophy, dilatation, scar, conduction disease or an electrical abnormality may develop gradually and remain clinically silent.
3
Triggers increase electrical instability
Exercise, fever, sudden noise, medicines or electrolyte disturbance can interact with a susceptible substrate. The relevant trigger differs between conditions and may reveal previously concealed disease.
4
Malignant arrhythmia starts
Triggered activity or re-entry can produce rapid ventricular tachycardia or fibrillation. Rapid VT may markedly reduce output, while ventricular fibrillation abolishes effective output and causes abrupt cerebral and coronary hypoperfusion.
5
Sudden collapse occurs
Loss of cerebral perfusion causes syncope and may produce brief tonic movements mistaken for epilepsy. Sustained ventricular fibrillation is cardiac arrest and, without prompt CPR and defibrillation, leads to irreversible organ injury and death.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Family red flags

Sudden unexplained death before age 50, multiple premature deaths, unexplained drowning/road crash, cardiomyopathy or known familial variant.

Symptom red flagsRed flag

Exertional or emotion-triggered syncope, palpitations with syncope, nocturnal agonal breathing or seizure-like episodes without neurological explanation.

Phenotypic clues

Unexplained LV hypertrophy/dilatation, RV scar/dilatation, conduction disease, ventricular ectopy or disproportionate troponin/scar episodes.

Channelopathy patterns

Prolonged QT, Brugada type 1 pattern, bidirectional/polymorphic exercise-induced VT or unexplained ventricular fibrillation.

Syndromic clues

Skeletal myopathy, deafness, neuropathy, dysmorphism, renal/hepatic disease or learning disability may indicate a multisystem genetic diagnosis.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Three-generation pedigree and record verificationFirst step
Why
Define inheritance pattern and identify relatives needing assessment.
Interpretation and limitations
Use confirmed diagnoses and circumstances; 'heart attack' in a young relative may conceal sudden arrhythmic death.
02
12-lead ECG with condition-specific provocation
Why
Detect conduction, repolarisation and channelopathy patterns.
Interpretation and limitations
Repeat or high-lead ECG, exercise testing or drug provocation belongs in an expert service when indicated.
03
Echocardiography and cardiac MRI
Why
Characterise ventricular morphology, function and scar.
Interpretation and limitations
CMR may reveal fibrosis or regional disease before global systolic dysfunction.
04
Ambulatory ECG and exercise testing
Why
Correlate symptoms and identify ventricular ectopy or exertion-triggered arrhythmia.
Interpretation and limitations
Use a protocol reaching the person's relevant workload while maintaining resuscitation capability.
05
Genetic testing with counselling
Why
Confirm an inherited diagnosis and enable cascade testing when a causal variant is found.
Interpretation and limitations
Pathogenic/likely pathogenic variants can guide relatives; negative testing does not exclude familial disease and a VUS is not predictive.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Vasovagal or orthostatic syncope

A prolonged upright posture, heat, pain, nausea and gradual prodrome favour reflex syncope. Collapse during exertion, supine events, palpitations or a family sudden death require cardiac assessment.

Epilepsy

Focal onset, prolonged post-event confusion or a characteristic neurological history supports seizure. Arrhythmic cerebral hypoperfusion can still cause tonic movements, so sudden exertional episodes merit ECG and family review.

Acute coronary syndrome

Coronary occlusion is a common acquired cause of ventricular arrhythmia and sudden collapse. Ischaemic symptoms, dynamic ST-segment change and coronary findings support it; troponin elevation alone after resuscitation is not specific for an acute occlusion.

Pulmonary embolism

Large emboli cause abrupt dyspnoea, syncope, hypoxaemia and sometimes cardiac arrest. Venous thromboembolic risk, right-heart strain and pulmonary vascular imaging identify the alternative mechanism.

Toxic or metabolic arrhythmia

Drug overdose, interacting QT-prolonging medicines and electrolyte disturbance can provoke ventricular arrhythmia without a primary inherited syndrome. A clear exposure and resolution after correction support an acquired cause, but a normal subsequent resting phenotype does not exclude concealed inherited susceptibility.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01FirstSymptomatic possible inherited conditionFirst stepExertional syncope, ventricular arrhythmia, abnormal ECG or unexplained cardiomyopathy.

1Assess urgent risk, obtain ECG and restrict high-intensity exercise until dangerous causes are evaluated.
2Take a detailed personal history and three-generation pedigree, including sudden-death circumstances and medicines.
3Perform echo, ambulatory ECG, exercise testing and CMR according to phenotype.
4Refer to an NHS inherited-cardiac-conditions service for diagnosis, genetic counselling and risk management.

02NextFamily after sudden unexplained deathSADS or unexplained sudden death with possible inherited cardiac cause.

1Confirm expert cardiac pathology, retain suitable DNA/tissue and reconstruct the death circumstances.
2Offer first-degree relatives clinical screening with history, ECG, exercise ECG and echocardiography as a minimum framework.
3Use CMR, ambulatory monitoring or provocation testing when the family phenotype or initial results indicate.
4Perform molecular autopsy/cascade testing with counselling and arrange age- and condition-specific follow-up.

03EscalationConfirmed high-risk phenotypeEscalationSurvived cardiac arrest, sustained VT, high-risk cardiomyopathy or actionable channelopathy.

1Treat reversible triggers and provide condition-specific medicine, fever, electrolyte and exercise advice.
2Use guideline risk models plus clinical markers; do not base ICD decisions on genotype or one test alone.
3Discuss ICD, ablation or other disease-specific treatment in an inherited-arrhythmia/cardiomyopathy multidisciplinary team.
4Offer cascade screening, reproductive counselling, a written emergency plan and psychological support.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Ventricular arrhythmia and sudden death

A concealed channelopathy or scarred cardiomyopathy may first present with ventricular tachycardia, fibrillation or cardiac arrest. Normal resting tests do not fully remove risk in a convincing family phenotype.

Progressive heart failure

Inherited myocardial disease may progress from subtle remodelling to systolic, restrictive or right-ventricular failure. Declining function can coexist with arrhythmic risk and requires phenotype-specific surveillance.

Atrial arrhythmia and embolic stroke

Atrial enlargement and myocardial disease promote atrial fibrillation or flutter. Rapid rates may destabilise ventricular function, while atrial stasis can lead to systemic thromboembolism.

Progressive conduction disease

Some genetic cardiomyopathies and multisystem disorders damage the atrioventricular conduction system before severe pump failure. Bradycardia, syncope or sudden asystolic events may require pacing assessment.

Unrecognised risk in relatives

Dominant inheritance and age-related penetrance mean asymptomatic relatives may carry clinically important risk. Failure to preserve post-mortem DNA or arrange appropriate family screening can miss opportunities to identify disease and reduce risk.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Repeat phenotype assessment at condition- and age-specific intervals because penetrance can be delayed.
Track syncope, palpitations, exercise tolerance, ICD therapies and new family diagnoses.
Use serial ECG, ambulatory monitoring, echo/CMR and exercise testing according to the phenotype.
Reinterpret genetic variants periodically through the genetics service; do not independently reclassify a VUS.
Review exercise, occupation, driving, pregnancy, fever and medicine-avoidance advice whenever circumstances change.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The proband matters

Testing an affected relative has a higher chance of an interpretable result than broad testing of an unaffected family member.

Phenotype can precede genotype

A negative panel does not erase a convincing familial cardiomyopathy; relatives may still need clinical surveillance.

VUS means uncertain

Do not use a VUS to clear or diagnose relatives; segregation and future evidence may later change classification.

Seizure mimic

Transient cerebral hypoperfusion from ventricular arrhythmia can cause tonic movements; exertional or sudden episodes deserve ECG review.

Autopsy is family care

Expert pathology and retained DNA can prevent speculative diagnoses and direct effective screening.

11Common pitfallsFrequent interpretation and management errors.

01
Reassuring a family after one normal ECG and echo.
02
Ordering a broad gene panel without phenotype or genetic counselling.
03
Using a variant of uncertain significance for predictive cascade testing.
04
Labelling exertional syncope as vasovagal without cardiac assessment.
05
Applying the same sports or ICD rule to every inherited condition.