title: Molecular biology of the long QT syndrome: impact on management.
abstract: The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions of adrenergic activation. Recently, the genes for the LQTS inked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQT1) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQT1 potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na+ channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na+ channel blocker such as mexiletine for LQT3 patients and of interventions such as K+ channel openers or increases in the extracellular concentration of potassium for LQT1 and LQT2 patients.
authors.affiliation: Department of Cardiology, University of Pavia, Policlinico S. Matteo IRCCS, Italy.
authors.forename: S G
authors.initials: SG
authors.lastname: Priori
authors.forename: C
authors.initials: C
authors.lastname: Napolitano
authors.forename: V
authors.initials: V
authors.lastname: Paganini
authors.forename: F
authors.initials: F
authors.lastname: Cantù
authors.forename: P J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D018674:Adrenergic Antagonists / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D015316:Genetic Therapy; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D008801:Mexiletine / Q000494:pharmacology; D008967:Molecular Biology; D009206:Myocardium / Q000166:cytology; D010455:Peptides / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D011188:Potassium / Q000097:blood / Q000627:therapeutic use; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D011941:Receptors, Adrenergic / Q000502:physiology; D012307:Risk Factors; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D013575:Syncope / Q000209:etiology; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy
chemical_list: D018674:Adrenergic Antagonists; D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011941:Receptors, Adrenergic; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013449:Sulfonamides; D008801:Mexiletine; C012746:anthopleurin-A; C063533:dofetilide; D011188:Potassium