Inherited Arrhythmia Syndromes

Long QT Syndrome

Long QT syndrome is one of the most common inherited arrhythmias, affecting approximately 1 in 2,000 individuals.³ Mean age at symptom onset is approximately 14 years, and SCD is the initial presentation in up to 13% of cases.⁴ Because there is no absolute cutoff value for a prolonged QTc, LQTS is often diagnosed by using the Schwartz scoring system, which combines clinical history and other electrocardiographic (ECG) findings.⁵ Seventeen genetically unique subtypes of LQTS have been identified; three of them (LQT1, LQT2, and LQT3) account for >90% of cases.⁶ Identification of the underlying genetic mutation in LQTS patients is clinically important because each subtype is associated with different triggering events, treatment responses, and survival rates.

The estimated 10-year mortality rate for untreated symptomatic LQTS is high, at nearly 50%.⁷ Proper treatment, however, can reduce the mortality rate to approximately 1%, highlighting the importance of early intervention.⁸ The primary treatment is with β-blockers (propranolol or nadolol).⁹ The effectiveness of β-blockers appears to vary by LQTS subtype, with the most benefit for patients with LQT1, LQT2, and LQT3 subtypes.¹⁰ Combining mexiletine with β-blockers has proven particularly beneficial for LQT2 and LQT3.^11,12 If β-blocker therapy fails, left cardiac sympathetic denervation is recommended; this is most effective against the LQT1 subtype.⁹ Implantable cardioverter-defibrillator (ICD) therapy is indicated for secondary prevention, but should also be considered for primary prevention in patients with high-risk characteristics (including but not limited to QTc >500 ms, LQT2 or LQT3 genotype, and young age at presentation).¹³

Short QT Syndrome

Short QT syndrome is rare, having first been described in 2000 and reported in only about 220 cases since then.^14,15 The typical cutoff value for short QTc is 360 ms in the presence of an appropriate clinical history or 330 ms in the absence of symptoms.¹⁶ Affected individuals are at increased risk of both ventricular and atrial arrhythmias, with slow atrial fibrillation resistant to cardioversion occasionally observed.¹⁴ The most common presentation is SCD or aborted SCD, observed in up to 34% of affected families.¹⁴ Several causative gene mutations have been implicated in affected families, although in most cases no responsible mutation is found.¹⁷ Treatment of symptomatic individuals includes ICD therapy for secondary prevention and quinidine for its QT-prolonging effects.^13,18 The role of treatment in asymptomatic patients is less clear, with further studies needed to accurately risk-stratify this population, given the overall low risk of SCD.^13,14

Brugada Syndrome

First described in 1992, BrS is characterized by right bundle branch block with ST-segment elevation in leads V₁ through V₃ and a high incidence of SCD.¹⁹ Symptoms typically occur at night or at rest. The estimated prevalence of BrS worldwide is 1 in 2,000 and even higher in Asian countries, where it is endemic.²⁰ The disorder occurs predominantly in males and, in endemic areas, is the leading cause of natural death in men younger than 40 years.²¹

The most prevalent BrS-associated genetic mutation (found in up to 25% of patients) occurs in SCN5A, a gene that encodes the I_Na sodium channel and is implicated in several other disorders, including LQT3.¹⁷ Three distinct ECG patterns have been associated with BrS; however, only one, consisting of a coved ST-segment elevation followed by a negative T wave (type 1), is diagnostic. In cases where the diagnosis is uncertain, the type 1 pattern can be induced by challenge with a sodium channel blocker such as ajmaline or flecainide.

Treatment for BrS includes ICD therapy (for patients with a history of ventricular arrhythmias), catheter ablation, and quinidine.¹³ Fever and certain sodium channel–blocking drugs may unmask BrS, and avoiding them is recommended. In asymptomatic patients with only an inducible type 1 pattern, electrophysiologic studies may help identify high-risk patients who might benefit from intervention.¹³

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia is characterized by recurrent exercise-induced bidirectional or polymorphic VT²² and is particularly malignant, causing SCD at initial presentation in up to 30% of patients and cardiac arrest by age 20 to 30 years in up to 50%.²³ The estimated prevalence of CPVT is 1 in 10,000.²⁴ In more than half of cases, a mutation in the gene encoding the ryanodine receptor is implicated; the consequent abnormal leakage of calcium from the sarcoplasmic reticulum leads to delayed afterdepolarizations and ventricular arrhythmias in response to known stressors.¹⁷ Unlike other inherited arrhythmias, CPVT is often associated with a normal resting ECG, which can make diagnosis difficult.

Pharmacologic therapy for CPVT consists of β-blockers (nadolol or propranolol) with the addition of flecainide in refractory cases.²⁵ Left cardiac sympathetic denervation is also beneficial in refractory cases.²³ Implantable cardioverter-defibrillator therapy for CPVT is complicated, because the shocks delivered can precipitate further electrical storm through a vicious cycle of continued adrenergic stimulation. Therefore, ICD therapy is recommended only for survivors of cardiac arrest or patients who remain highly symptomatic despite maximal medical therapy.¹³

Early Repolarization Syndrome

Early repolarization (ER), characterized by J-point elevation and an upsloping ST segment, has long been considered a benign ECG finding and is seen in up to 13% of the general population.²⁶ However, recent evidence suggests that it increases the risk of SCD.^27–29 Early repolarization syndrome, defined as ER accompanied by unexplained ventricular arrhythmias, is now recognized as a distinct inherited arrhythmia. Although ER is common in the general population, ERS is rare, with an estimated prevalence of 0.5 per 100,000 in one study.³⁰ Only a handful of genetic mutations have been associated with ERS, and there is currently no role for routine genetic testing for them.²⁶ Early repolarization syndrome is associated with a high risk of recurrent ventricular arrhythmias (up to 40%),²⁸ and its treatment is limited to ICD therapy for secondary prevention and to quinidine in refractory cases.^13,16 Implantable cardioverter-defibrillator therapy can also be considered in asymptomatic patients with a strong family history of SCD and high-risk ECG features such as high J-wave amplitude and a horizontal/descending ST segment.¹⁶

Idiopathic Ventricular Fibrillation

Idiopathic ventricular fibrillation is defined as VF of unknown origin despite extensive diagnostic testing and exclusion of other primary arrhythmia syndromes. Historically, this definition has encompassed many other inherited arrhythmias that are now recognized as distinct, including BrS, LQTS, SQTS, and most recently ERS.³¹ The true prevalence of IVF is therefore difficult to estimate. Its pathogenesis is unclear, although there is evidence that in some patients short-coupled premature ventricular contractions can elicit torsades de pointes and VF.³¹ Microstructural cardiomyopathic areas acting as a substrate of VF re-entries may also play a role.³² As with ERS, treatment consists of ICD therapy for secondary prevention and quinidine.^13,31 In addition, ablation can be an effective treatment for IVF initiated by premature ventricular contractions with a consistent QRS morphology.¹³

Conclusion

Inherited arrhythmias have wide clinical variability and are therefore challenging to diagnose and to manage. A better understanding of their underlying genetic causes has led to advances in their detection and treatment and to substantial reductions in associated morbidity and mortality. However, better means of identifying high-risk patients and reducing unnecessary treatment-related harm are still needed. Continued research into the genetic and cellular mechanisms underlying these disorders will help to achieve that goal and identify potential targets for improved disease-specific treatments.

★ CME Credit

Section editor: Mohammad Saeed, MD, FACC

Meeting presentation: Presented at The Ali Massumi Cardiac Arrhythmia Symposium; Houston, 15 February 2020.

CME credit: To obtain CME credit, you must 1) carefully read the other CME-designated articles marked with a ★ in this issue of the Journal, and then 2) click this link for instructions on completing the assessment survey.