Lecture 2 Inherited Arrhythmias

Introduction to Genetic Evaluation and Testing in Inherited Arrhythmia

  • Erin Miller, genetic counselor in cardiology at Cincinnati Children's Hospital.

  • Focus of the lecture: Genetic evaluation and testing for inherited arrhythmias.

    • REALL: inherited arrhythmias are non-ischemic heart disease

Objectives

  1. Clinical Diagnosis of Inherited Heart Rhythm Conditions

    • Discuss Long QT syndrome, CPVT, and Brugada syndrome.

  2. Risk Factors for Long QT Syndrome

    • Identify increased risk factors for cardiac events.

  3. Genetic Testing and Counseling

    • Approaches to genetic testing for inherited arrhythmias.

Long QT Syndrome (LQTS)

  • Definition of LQTS

    • a disorder of the heart rhythm (arrhythmia) that can cause chaotic, fast heartbeat. Can be life threatening

  • Definition of QT Interval

    • Measure of time for ventricles to contract and relax during one heartbeat (measured in milliseconds).

    • Normal QT interval is about a third of the entire heartbeat.

    • In LQTS, the QT interval is longer than it should be, i.e takes ventricles too long to “recharge”

  • Characteristics

    • Prolongation of QT interval, seen on electrocardiograms (EKG).

    • Symptoms: Increased risk for fainting (syncope) and sudden cardiac death.

    • Specific arrhythmia: Torsades depointes, a dangerous fast heart rhythm originating in the ventricles.

  • Prevalence

    • Affects approximately 1 in 2,000 to 3,000 individuals.

  • Guidelines for QT Interval Length

    • QT interval >450 ms (women), >460 ms (men) indicates LQTS.

    • QT interval can vary based on age and gender.

    • Use QTc (QT corrected for heart rate) for assessment.

      • resting heart rate varies by individual and can influence the QTc calculation, making it essential to consider when evaluating patients for long QT syndrome.

  • Clinical Diagnosis

    • Schwartz Score determines pre-test probability using clinical features and EKG findings.

      • a score higher than 3.5 indicates higher probability of LQTS

    • Diagnosis may occur without a clear mutation.

    • Prolonged QT >500 ms on multiple EKGs qualifies for diagnosis.

  • Types of LQTS

    • Type 1 (60% cases): KCNQ1 mutations, triggered by exercise or emotions.

    • Type 2 (35% cases): KCNH2 mutations, triggers include exercise, strong emotions, or startle from sleep.

      • tend to be associated with risk for sudden cardiac arrest (SCA), higher in women than in men

    • Type 3 (least common): SCN5A mutations, symptoms occur during rest or sleep.

    • Symptoms and EKG findings might overlap, requiring genetic testing for type confirmation.

  • Syndromes related to LQTS

    • LQTS is umbrella, lits of conditions that fall under it

      • Jervell and Lange-Nielsen syndrome = type 1 LQTS from autosomal recessive pathogenic variant in KCNQ1

      • Andersen-Tawail syndrome = autosomal dominant, KCNJ2 pathogenic variant

EKG Findings and Symptoms in LQT

  • Characteristic EKG Patterns

    • Type 1: Broad-based T-wave.

    • Type 2: Notched T-wave.

    • Type 3: Late peaking T-wave.

  • Torsades

    • Polymorphic ventricular tachycardia, characterized by a twisting point pattern.

  • Clinical Symptoms

    • Syncope, seizures, and varying expressivity in symptoms.

    • Common genetic variants can act as modifiers to disease presentation.

Evaluation and Risk Assessment for LQTS

  • Family history analysis for fainting, seizures, sudden deaths, heart events, and accidents.

  • Medication Review

    • Identifying QT-prolonging medications (e.g., certain SSRIs, antibiotics).

  • Genetic Background

    • Several known genes associated with LQTS, consolidating into eight key genes for genetic testing.

      • initially 17 genes thought to be associated, now ClinGen lists 8 as moderate, strong, or definitive association

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

  • Definition and Mechanism

    • Inherited arrhythmia disorder

    • Catecholamines (e.g., epinephrine) trigger arrhythmias under emotional or physical stress.

      • catecholamines = chemicals that are classified as aromatic amines, including many types of neurotransmitters such as dopamine and norepinephrine, which play significant roles in the body's response to stress and can influence heart rhythm.

      • These disorders often result from genetic mutations that affect ion channels in cardiac cells, leading to abnormal electrical activity and increased susceptibility to arrhythmias.

    • Ventricular tachycardia = an arrhythmia where the ventricles beat too fast. Can be life threatening.

    • CPVT proposed to be potential cause of sudden death in otherwise healthy kids

  • Prevalence

    • Affects ~ 1 in 10,000; tends to present in childhood (ages 7-12).

  • Clinical Diagnosis

    • Normal EKG, normal echo, stress testing is essential to provoke VT.

  • Genetic Testing

    • ~65% of CPVT cases linked to mutations in RYR2 gene (autosomal dominant).

    • Secondary causes include CASQ2, TRDN, TECRL mutations (mostly recessive).

    • Additionally, genetic testing can help identify other potential mutations, such as those in the CASQ2 gene, which may also contribute to arrhythmias and guide appropriate management strategies.

  • Management

    • Beta-blockers (e.g., Nadolol), lifestyle modifications, possible implantable cardioverter-defibrillator (ICD).

      • beta blockers work to slow down the heart rate and reduce the workload on the heart, which can significantly decrease the frequency and severity of arrhythmias.

Brugada Syndrome

  • Characteristics

    • Arrhythmia condition that can be inherited characterized by increased irregular heartbeat rhythms in the lower chambers (ventricles)

    • Caused by sodium channel abnormalities

    • Symptoms may include fainting, palpitations, or sudden cardiac arrest, often triggered by fever or certain medications.

    • Diagnosis is typically confirmed through an electrocardiogram (EKG) showing characteristic ST-segment elevation.

    • Penetrance: approximately 30%

  • Prevalence

    • Estimated 1 in 5,000 to 10,000, commonly seen in adult males.

  • Diagnostic Criteria

    • Identification of Type 1 Brugada EKG pattern and presence of dangerous arrhythmias or significant family history.

  • Genetic Testing

    • SCN5A gene identified as a key player, but other genetic associations have been refuted.

    • Testing yield is 15%-30%.

  • Management

    • ICD placement for individuals with syncope/cardiac arrest history. Avoid sodium channel blockers and medications that exacerbate symptoms.

Conclusion

  • Key points: Long QT syndrome, CPVT, and Brugada syndrome present serious inherited arrhythmia conditions with potentially fatal outcomes.

  • Genetic testing and counseling are recommended based on current guidelines and specific gene associations.

  • Continuous evaluation and monitoring are essential for effective management and treatment plans.