The inherited long QT syndrome: from ion channel to bedside

The inherited long QT syndrome is caused by mutations of at least 5 ion channel genes. Mutations of the cardiac sodium ion channel gene and 3 potassium channel genes have been identified to this time. A genetic locus on chromosome 4 has been identified, but no gene has been discovered as of yet. More than 120 mutations of the genes have been discovered. The majority of cases are inherited by autosomal dominant transmission. Syncope occurs in approximately two-thirds of gene carriers, with sudden death in 10% to 15% of untreated patients. The primary electrophysiologic disturbance is delayed recovery of the action potential, because of diverse physiologic perturbations dependent upon the specific ion channel and mutation. The delayed recovery predisposes individuals to the development of early afterdepolarizations and initiation of torsade de pointes arrhythmias. The torsade produces the syncope and sudden death. Patients with self-terminating torsade have syncope, whereas those whose torsade degenerates to ventricular fibrillation experience sudden death. The torsade maintenance appears to be because of complex reentry or repetitive triggered beats, both of which have been proposed as capable of explaining the unique and characteristic QRS morphology of torsade. It is proposed that the degree of dispersion of recovery at the time of torsade determines whether the torsade degenerates to ventricular fibrillation or self-terminates. The signs of long QT syndrome are prolongation of the QT interval on the electrocardiogram and abnormalities of T wave morphology. QTc values average 0.49 seconds and vary somewhat by genotype. Approximately 12% of long QT gene carriers have a normal QTc, < or =0. 44 seconds. Thus, a normal QTc interval does not exclude long QT syndrome. T wave morphology is relatively characteristic for each genotype. Diagnosis is likely with a QTc > or =0.48 seconds in females and > or =0.47 seconds in males. Values between 0.41 and 0.46 seconds require additional evaluation, as the disorder can neither be excluded nor made with those QTc intervals. Diagnosis is enhanced by identification of T wave abnormalities consistent with long QT syndrome. The principal treatment is beta-blocker therapy. Appropriate dosing, with ascertainment of efficacy and compliance with administration, are the key elements in therapeutic success. Molecular physiology-based strategies are being considered, including the use of sodium channel blockers in LQT3 and potassium administration in LQT1 patients.