13th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 1998

January 24-31, 1998
Marilleva, Trento, Italy

RT-125

Advances in cardiac arrhythmias. From molecular biology to clinical management

Nabil El-Sherif.
Cardiology Division, Department of Medicine, State University of New York Health Science Center and Veterans Affairs Medical Center, New York, USA

Molecular, ionic and electrophysiologic basis of polymorphic ventricular tachyarrhythmias (torsade de pointes) in the long QT syndrome (LQTS)

The idiopathic or congenital LQTS is an inherited disease characterized by prolonged ventricular repolarization and a high risk for sudden cardiac death. Most of the life-threatening arrhythmias in LQTS occur during physical or emotional stress, although in some families, sudden death occurs during sleep. Studies of the mechanisms underlying arrhythmias in LQTS have integrated clinical science, basic electrophysiology, and molecular genetics. Understanding of these mechanisms not only would contribute to improved therapy for patients with this intriguing, albeit uncommon, disease but also would provide information important for understanding the more prevalent acquired form of LQTS.

Mutations causing LQTS have been identified in at least three genes, each encoding a cardiac ion channel¹. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease. Mutations in the human ether-à-go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KvLQT1. A mutation of KvLQT1 produces a defect in the subunit that coassembles with the product of min K to form the channel responsible for I_Ks². The SCN5A mutations result in defective sodium channel inactivation, whereas HERG and KvLQT1 mutations result in decreased outward potassium current.

Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation.

Irrespective of the underlying genetic abnormality in the LQTS the in vivo electrophysiologic mechanism of TdP seems to be similar. In a recent study of the canine AP-A model of LQTS, a surrogate for LQT3, tridimensional mapping of activation and recovery patterns has revealed the existence of spatial dispersion of repolarization in the ventricular wall and differences in regional recovery in response to cycle length changes that were exaggerated in the presence of LQTS³. The initial beat of TdP consistently arose as focal activity from a subendocardial site (an early afterdepolarization-triggered beat), whereas subsequent beats were due to successive reentrant excitation. The latter was due to infringement of a focal activity on the spatial dispersion of repolarization resulting in functional conduction block and circulating wavefronts. The twisting pattern of the QRS during TdP was shown to coincide with transient bifurcation of a predominately single rotating scroll into two simultaneous scrolls involving both the right and left ventricles⁴.

Recently, several studies began to evaluate the impact of the findings on the nature of genetic defects in the congenital LQTS on management of those patients. For example, the drug mexiletine, a sodium channel blocker, was shown to shorten the QT interval in patients with LQT3 syndrome but not LQT2 patients⁵, while potassium supplement to increase the level of extracellular potassium may be bene-ficial in patients with the LQT2 syndrome⁶.