title: A molecular basis for the therapy of the long QT syndrome.
abstract: The long QT syndrome (LQTS) is a familial disease characterized by abnormally prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmia. Recently, molecular biology studies brought major advancements in the understanding of the pathophysiologic mechanisms of this disease. The genes for the LQTS linked to chromosomes 3 (LQT3). 7 (LQT2) and 11 (LQT1) were identified as SCNSA, the cardiac sodium channel gene and as HERG and KVLQT1 potassium channel genes. We developed a cellular model in which ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. The effects of sodium channel blockade and rapid pacing were then studied showing a pronounced action potential shortening in response to mexlietine and during rapid pacing only in antopleurin-treated cells but no in dofetilide-treated cells. On this experimental basis, we tested the hypothesis that QT interval would behave differently during similar intervention in LQT3 and LQT2 patients. Results showed that 1) mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients and 2) LQT3 patients shortened their QT interal in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. They also suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cathecolamines with the insufficient adaptation of their QT interval when heart rate increases.
authors.affiliation: Dipartimento di Cardiologia, Facolta di Medicina e Chirurgla, Università degil Studi di Pavia, Policlinico San Matteo IRCCS, Italy.
authors.forename: S G
authors.initials: SG
authors.lastname: Priori
authors.forename: C
authors.initials: C
authors.lastname: Napolitano
authors.forename: P J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D006168:Guinea Pigs; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D008801:Mexiletine / Q000494:pharmacology; D008954:Models, Biological; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics
chemical_list: D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine