Overview of Channelopathies

Channelopathies are a group of genetic, autoimmune, or inflammatory conditions that alter cardiomyocyte ion channel function in a manner that predisposes to bradyarrhythmias or tachyarrhythmias in the absence of a structural heart disorder. Sudden cardiac death may occur.

The ion channels affected include those responsible for the inward sodium or calcium currents and those responsible for the outward potassium current. Either gain of function or loss of function in these ion channels, particularly when the abnormal channels are unevenly distributed, fosters abnormal electrophysiological environments. The abnormal electrophysiology may be favorable to one or both of the following:

The most common genetic channelopathies are the Brugada syndrome (BrS) Brugada Syndrome Brugada syndrome is an inherited channelopathy causing an increased risk of ventricular tachycardia (VT) and ventricular fibrillation (VF) leading to syncope and sudden death. (See also Overview... read more , catecholaminergic polymorphic ventricular tachycardia (CPVT) Catecholaminergic Polymorphic Ventricular Tachycardia Catecholaminergic polymorphic ventricular tachycardia is a genetic disorder affecting intracellular calcium regulation in cardiac tissue. Patients are predisposed to ventricular tachyarrhythmias... read more , early repolarization syndrome (ERS) Early Repolarization Syndrome Early repolarization syndrome is a genetic disorder of cardiomyocyte ion channel function (channelopathy). Patients are predisposed to polymorphic ventricular tachycardia (VT) and ventricular... read more , idiopathic ventricular fibrillation (IVF) Ventricular Fibrillation (VF) Ventricular fibrillation causes uncoordinated quivering of the ventricle with no useful contractions. It causes immediate syncope and death within minutes. Treatment is with cardiopulmonary... read more , isolated progressive cardiac conduction disease (isolated PCCD Isolated Progressive Cardiac Conduction Disease Isolated progressive cardiac conduction disease (PCCD) refers to a group of genetic disorders that involve progressively worsening defects in cardiac conduction, including sinus node dysfunction... read more ), long QT interval syndromes (LQTS) Long QT Interval Syndromes The long QT interval syndromes (LQTS) result from any congenital or acquired disorder of cardiac ion channel function or regulation (channelopathy) that prolongs ventricular myocyte action potential... read more , and short QT interval syndrome (SQTS) Short QT Interval Syndromes The short QT interval syndromes (SQTS) are extremely rare congenital or very rarely acquired disorders of cardiac ion channel function or regulation that shorten ventricular myocyte action potential... read more . Together, these genetic channelopathies account for approximately 10% of sudden cardiac deaths.

Autoimmune disorders, including Sjogren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes ... read more and systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , and inflammatory disorders producing cytokinins that affect cardiomyocyte ion channel function are increasingly being recognized. Anti-Ro/SSA antibodies may produce a long QT interval syndrome by inhibiting the human ether-a-go-go-related gene (hERG) related outward potassium channel, and transplacental exposure to these antibodies in utero is responsible for congenital AV block. Autoimmune antibody production and inflammatory cytokinins may also be responsible for temporal variability in arrhythmia propensities, such as the deleterious effects of fever in patients with Brugada syndrome.

Diagnostic evaluation for genetic channelopathies usually includes ECG, ambulatory cardiac monitoring, and sometimes exercise testing. Genetic testing is frequently done but may not be recommended if its sensitivity for a particular disorder is low. Patients diagnosed with a channelopathy should have regular follow-up with ECG and ambulatory cardiac monitoring to detect occult arrhythmias.

Family members are at risk of disease and should have clinical evaluation (ie, to detect symptoms suggestive of arrhythmia), ECG, ambulatory monitoring, and, sometimes, exercise testing to identify the presence of disease prior to its expression as sudden death. Genetic testing of family members is done when the index case has a known mutation. Typically, parents and siblings are tested first and then other relatives are tested based on results of parent testing and the mode of inheritance (cascade testing). Family members also require ongoing clinical monitoring for development of arrhythmias unless the genetic mutation is absent.

Treatments depend on disease manifestations, but all patients should avoid known triggers (eg, exercise, certain drugs). Patients with clinical or ECG findings of significant ventricular arrhythmias typically require an implantable cardioverter-defibrillator Implantable Cardioverter-Defibrillators (ICD) The need for treatment of arrhythmias depends on the symptoms and the seriousness of the arrhythmia. Treatment is directed at causes. If necessary, direct antiarrhythmic therapy, including antiarrhythmic... read more , often one with pacemaker functionality. Some disorders benefit from beta blockade and/or other antiarrhythmic drugs Medications for Arrhythmias The need for treatment of arrhythmias depends on the symptoms and the seriousness of the arrhythmia. Treatment is directed at causes. If necessary, direct antiarrhythmic therapy, including antiarrhythmic... read more .