The long QT syndrome: new diagnostic and therapeutic approach in the era of molecular biology

The idiopathic long QT syndrome is a congenital disease characterized by prolongation of the QT interval and by stress-induced syncopal episodes caused by the development of "torsades de pointes". Over the last decade, the great advances in the field of molecular biology have made it possible to elucidate the genetic causes of the disease. In particular, three genes have been implicated in the pathogenesis of the disease: SCN5A (LQT3), encoding for the cardiac sodium channel and located on chromosome 3, HERG (LQT2), encoding for a cardiac potassium channel (Ikr) and located on chromosome 7 and KVLQT1 (LQT1), located on chromosome 11 and encoding for a cardiac potassium channel whose electrophysiologic profile is still undefined. Within each of these genes several different mutations have been identified and subsequently expressed to determine the electrophysiological changes induced by the mutation in the normal function of the channels. These studies have suggested that LQT3 is caused by alterations in the inactivation of cardiac sodium channels while LQT2 is caused by a reduction in the delayed rectifier potassium current. Based on this evidence, we developed the first cellular model for LQTS in order to provide a mean of assessing the effect of different interventions in two different forms of disease, LQT2 and LQT3. We exposed guinea pig ventricular myocytes to anthopleurin, a toxin that interferes with the inactivation of INa, and to dofetilide, a selective blocker of Ikr, obtaining a prolongation of cellular repolarization with both drugs. We then exposed cells to a Na+ channel blocker, mexiletine, which significantly reduced APD in cells treated with anthopleurin while it did not modify the prolongation induced by dofetilide. In addition, anthopleurin-treated cells demonstrated a greater shortening of APD to rapid pacing than both control and dofetilide-treated cells. Based on this experimental evidence, we tested the same therapeutic interventions, mexiletine and pacing, in fifteen genetically characterized LQTS patients. Mexiletine significantly shortened the QT interval in LQT3 patients but not in LQT2 patients. When we examined the response to an increase in heart rate, we found that LQT3 patients had a more shortened QT interval in response to heart rate changes than LQT2 patients and than healthy controls.