Chapter 60 - Molecular Basis of Inherited Long QT Syndromes and Cardiac Arrythmias

Abstract

This chapter focuses on the molecular basis of long QT syndromes (LQTS) and cardiac arrythmias. The molecular genetic approach including linkage analysis performed in large families has identified five loci responsible for the LQTS. Since the first discovery of a locus associated with congenital (LQTS), at least 14 different loci and four different genes have been held accountable for inherited cardiac arrhythmias. These four genes all encode for ion channel subunits involved in generating the cardiac action potential.. The phenotype of both Jervell and Lange-Nielsen (JLN) and Romano–Ward (RW) LQTS is characterized by a prolonged QT duration on a surface electrocardiograph (ECG) and by an abnormal T wave morphology. Clinically, the QT interval is longer in females as compared to males, and in addition, a moderate sinus bradycardia is often present. QT prolongation could be considered per se as a minor problem however, QT prolongation reveals a major abnormality of cardiac electrical repolarization, which may eventually lead to complex cardiac ventricular arrhythmias and death. The LQTS is characterized by paroxystic life-threatening polymorphic ventricular tachycardias such as torsades de pointes. Syncopes typically occur during stress or physical exercise and for those prone to syncope, the mortality rate can be as high as 50% within the first year in the absence of treatment.