When genetic mutations occur in the proteins of ion channels or their regulatory channels, their function may increase or decrease abnormally. This leads to irregular depolarization or repolarization processes in myocardial cells, resulting in the prolongation or shortening of the action potential duration, causing arrhythmias or even sudden death, which is known as channelopathies. With advancements in genetic testing, many patients who have unexplained syncope or even cardiac sudden death, without organic heart disease, have been found to have genetic variations, especially those with a family history. These conditions are now collectively referred to as inherited arrhythmia syndromes.
Long QT syndrome
Long QT syndrome (LQTS) can be congenital or acquired. Most congenital cases are familial hereditary diseases caused by mutations in one or more genes. Acquired cases may also have an underlying genetic susceptibility, with QT interval prolongation caused by myocardial ischemia, electrolyte disturbances, and various medications (quinidine, amiodarone). Clinically, LQTS is manifested by syncope and/or sudden death. Syncope is related to exercise, emotional stress, or excitement, though some patients may experience it during rest or sleep. For asymptomatic patients with a family history of complex ventricular arrhythmias, early-onset cardiac sudden death, or a corrected QT interval (QTc) > 500ms, treatment with the maximum tolerated dose of non-selective β-blockers, such as propranolol and nadolol, is recommended. Patients who have experienced syncope or cardiac arrest should receive ICD implantation and β-blocker therapy.
Brugada syndrome
Familial Brugada syndrome (BrS) has been linked to gene mutations in sodium and calcium channels. Clinically, it presents with recurrent syncope and is a major cause of sudden death in young adults without structural heart disease. Patients typically have normal cardiac structures, with episodes often triggered by excessive alcohol consumption or fever. The ECG shows a downsloping or saddleback ST segment elevation in leads V1 to V3. Genetic testing for the SCN5A gene is recommended for suspected cases. Currently, there is no effective treatment for BrS. Patients with syncope, cardiac arrest, ventricular flutter, or ventricular fibrillation should receive ICD implantation. Quinidine may be used if frequent ICD discharges occur.
Figure 1 Brugada syndrome
A. Downsloping ST segment elevation in lead V1 (indicated by the arrow); B. Saddleback ST segment elevation in lead V1 (indicated by the arrow)
Catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited ventricular tachycardia, often without significant structural heart disease. It is caused by mutations in genes encoding proteins involved in intracellular calcium regulation, leading to autosomal dominant inheritance. Symptoms such as palpitations, syncope, and cardiac arrest can occur from childhood, and are often triggered by exercise or emotional stress, though some patients may experience symptoms at rest. The ECG typically shows no specific features. Patients should avoid strenuous exercise and receive β-blockers. If drug therapy fails to control ventricular arrhythmias, left cardiac sympathetic denervation should be considered. ICD implantation may be considered for patients who continue to experience cardiac arrest, recurrent syncope, bidirectional VT, or polymorphic VT despite optimal medical therapy and/or left cardiac sympathetic denervation.
Short QT syndrome
Short QT syndrome (SQTS) is an autosomal dominant ion channelopathy caused by single-gene mutations. Clinically, it presents with palpitations, dizziness, and recurrent syncope and/or sudden cardiac death. Diagnosis is established with a QTc interval ≤ 320ms, or a QTc interval between 320 - 360ms with at least one of the following clinical criteria:
- Presence of a pathogenic gene mutation
- Diagnosis of SQTS or family history of sudden cardiac death before age 40
- Survival from ventricular tachycardia/ventricular fibrillation (VF) without structural heart disease
Asymptomatic patients with a short QTc interval may not require treatment. If cardiac arrest or sustained VT occurs, ICD implantation is preferred. For patients unable to receive an ICD, quinidine may be used to reduce VT occurrence.
Early repolarization syndrome
Early repolarization syndrome (ERS) is an abnormal repolarization pattern on the ECG, considered a physiological variant. It is characterized by J-point elevation ≥ 1mm in two or more contiguous inferior and/or lateral leads. Most patients with early repolarization do not have an increased risk of ventricular arrhythmias and typically do not require intervention. In patients with a history of cardiac arrest or documented polymorphic VT or idiopathic VF, ERS can be diagnosed. Patients with a family history of early-onset cardiac sudden death or those who have experienced syncope or cardiac arrest due to ventricular arrhythmias should receive ICD implantation, and quinidine may be used for recurrent or frequent VT/VF episodes.
Figure 2 Early repolarization
The arrow in lead II indicates J-point elevation.