Cardiac Channelopathies: Sudden Cardiac Death in the Young

Channelopathies

• Channelopathies are the genetic disorders of the heart which contribute to the development of cardiac arrhythmias. 
• Development of cardiac arrhythmias is the very important abnormality associated with channelopathies.
  • Very dangerous
  • Very innocuous
  • Predispose to the potentially lethal stroke or embolism. Whenever there's arrhythmia, there will be stasis of blood within the heart which will lead to thrombus and further contribute to thrombus embolism resulting in stroke or embolism. Also contributes to life threatening conditions that may result in sudden cardiac death.
• This sudden cardiac death occurring due to arrhythmias is the most important cause of the death in both developing and developed countries.

Sudden Cardiac Death in the Young

• The important differential diagnosis - channelopathies.
• It can be due to structural cardiovascular anomalies.
  • Can be found under autopsy.
  • Example - Hypertrophic Cardiomyopathy.
  • But there are no structural cardiovascular anomalies.
• In sudden cardiac death, which occurs secondary to channelopathies the heart appears to be absolutely normal even at autopsy time. 30-50% sudden cardiac deaths are unexplained which could be channelopathies.
  • They are very lethal and inheritable causes of arrhythmias.
  • These contribute to cardiac channelopathies.
• Cardiac channelopathies includes
  • Congenital long-QT syndrome (LQTS)
  • Brugada syndrome (BrS)
  • Catecholaminergic polymorphic ventricular tachycardia (CPVT)
  • Short QT
  • Drug induced LQTS.

The QT- Opathies

• It can be long QT syndrome and short QT syndrome.
• Normal QT interval - 360-440 msec.
• QT interval >460 msec - Long QT syndrome
• QT interval <360 msec - Short QT syndrome

Congenital LQTS

• It comprises a group of cardiac channelopathies characterised by delayed repolarization of myocardium.
• QT prolongation
  • Duration of QT interval - >480 msec.
  • QTc stands for corrected QT interval.
• Patients with Long QT syndrome are at increased risk of arrhythmias.
  • Decreased cardiac output causing Syncopal attacks.
  • Seizures due to reduced blood supply to the cerebral parenchyma. Ultimately, patients land up in sudden cardiac death.
• Congenital LQTS patients have a structurally normal heart.
• The incidence of LQTS may exceed 1 in 2500 persons.
• 12- lead surface ECG - QT prolongation may or may not manifest on the ECG.
• If it manifests, then there is a repolarization abnormality.
• Triggers include:
  • Exertion
  • Swimming
  • Emotion
  • Auditory stimuli, Like listening to alarm clock
  • The postpartum period.
• These triggers make the heart electrically unstable, and individuals may land up in potentially life threatening arrhythmias which leads to sudden cardiac death.
• The type of arrhythmia they develop because of QT prolongation - polymorphic ventricular tachycardia i.e., Torsades de pointes.
  • It contributes for individuals to develop sudden cardiac death.
• Cardiac rhythm having QT prolongation with polymorphic ventricular tachycardia.
  • Most often it returns to normal spontaneously.
  • Intervention is not required.
  • Occasionally there can be syncopal attacks. Transient episode
  • 5% of individuals left untreated, go into a state of fatal arrhythmias.
  • In 95% of individuals, the rhythm returns to normal.
• Warning signs responsible for sudden cardiac death
  • It includes history of Exertional syncope or Family history of premature sudden cardiac death.
• There are major and minor LQTS. Major LQTS are classified as
  • LQT1
  • LQT2
  • LQT3

Genetic Basis for Long-QT Syndrome

• It is an inherited disorder.
• It is either autosomal dominant or autosomal recessive or sporadic.
• If it is a heterogeneous disorder and is inherited autosomal dominant - Previously known as Romano ward syndrome.
• If it is inherited as autosomal recessive – Called as Jervel & Lange Nielsen syndrome.
  • They have hearing abnormality in the form of sensorineural hearing loss. Along with cardiac abnormalities.
• In 5-10% of patients, the mutation is sporadic germline mutation.

Extremely Rare Multisystem Disorders- Long QT interval

• Timothy syndrome
  • Formally known as LQT8
  • It is a rare form.
• Andersen- Tawil syndrome
  • Formally known as LQT7.
  • They have prolonged QU intervals.
• Ankyrin-B syndrome
  • Previously known as LQT4
• Approximately, 75% of patients with a clinically robust diagnosis of LQTS host either loss of function or gain of function mutations in one of three major LQTS genes.

Minor Long QT Syndrome

• In these cases, the QT interval is > 480 msec.
• Green boxes represent gain of function.
• Blue boxes represent loss of function/mutation.
• Pink colour is Sodium channelopathies. I.e., SCN5A
• Yellow or orange colour is potassium channelopathies.
• Purple ones are calcium channelopathies.
• BrS stands for Brugada syndrome. Due to gain of function of KCNE3 and KCND3.
• Brugada syndrome can also be due to calcium channelopathies or sodium channelopathies. In Brugada syndrome - Sodium, potassium and calcium channels are being affected.
  • Gain of function is only seen in potassium channels.
  • Loss of function is seen in calcium and sodium channels.
• Sodium channelopathies apart from Brugada syndrome are LQTS i.e., LQT3
  • LQT3 is the gain of function of the sodium channel.
• CCD stands for cardiac conduction disorder.
• SSS stands for sick sinus syndrome.
• In calcium channelopathies there is both gain and loss of function.
• Gain of function will be LQTS and Timothy syndrome (TA).
• Loss of function of calcium channels - Brugada syndrome, short QT syndrome.
• KCNJ2 is also a form of potassium channelopathies.
• ATS stands for Anderson Tawil syndrome.
  • Loss of function of KCNJ2
• SQTS and atrial fibrillation are gains of function of KCNJ2.

Genotype- Phenotype Correlates in Long-QT Syndrome

• Major LQTS - QT1, QT2, Qt3.
• They contribute to almost 75%.
  • KCNQ1-35%
  • KCNH2-30%
  • SCN5A-10%
• These encodes for ion channels that are critically responsible for orchestration of the cardiac action potential.
• For LQT1, the trigger is swimming, exertion/ emotion.
  • There will be Prolong QT syndrome. Development of polymorphic ventricular tachycardia and Torsades de pointes. Results in sudden cardiac death.
• In LQT2, the trigger is an auditory trigger and postpartum period.
• In LQT3, the trigger appears in sleep or resting conditions.
  • Sodium channelopathies
• LQT1 and LQT2 are potassium channelopathies.

Treatment

In all LQTS, the first line of drug is beta blockers. Especially, in LQT1 the drug of choice is beta blockers. In LQT2, LQT3 the beta blockers are moderately protective. Additional treatment options of LQT3:

• Mexiletine (anti arrhythmic.)
• Flecainide (anti arrhythmic.)
• Ranolazine (Anti anginal drug)

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