PMID- 8952843 OWN - NLM STAT- MEDLINE DCOM- 19970109 LR - 20131121 IS - 0003-9683 (Print) IS - 0003-9683 (Linking) VI - 89 IP - 9 DP - 1996 Sep TI - A molecular basis for the therapy of the long QT syndrome. PG - 1185-7 AB - 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. FAU - Priori, S G AU - Priori SG AD - Dipartimento di Cardiologia, Facolta di Medicina e Chirurgla, Universita degil Studi di Pavia, Policlinico San Matteo IRCCS, Italy. FAU - Napolitano, C AU - Napolitano C FAU - Schwartz, P J AU - Schwartz PJ LA - eng PT - Journal Article PL - France TA - Arch Mal Coeur Vaiss JT - Archives des maladies du coeur et des vaisseaux JID - 0406011 RN - 0 (Adrenergic beta-Agonists) RN - 0 (Anti-Arrhythmia Agents) RN - 0 (Potassium Channel Blockers) RN - 0 (Potassium Channels) RN - 0 (Sodium Channel Blockers) RN - 0 (Sodium Channels) RN - 1U511HHV4Z (Mexiletine) SB - IM MH - Action Potentials MH - Adrenergic beta-Agonists/pharmacology MH - Animals MH - Anti-Arrhythmia Agents/pharmacology MH - Chromosomes, Human, Pair 3/genetics MH - Chromosomes, Human, Pair 7/genetics MH - Guinea Pigs MH - Heart Rate MH - Humans MH - Long QT Syndrome/*drug therapy/genetics/physiopathology MH - Mexiletine/pharmacology MH - *Models, Biological MH - Potassium Channel Blockers MH - *Potassium Channels/genetics MH - Sodium Channel Blockers MH - *Sodium Channels/genetics EDAT- 1996/09/01 00:00 MHDA- 1996/09/01 00:01 CRDT- 1996/09/01 00:00 PHST- 1996/09/01 00:00 [pubmed] PHST- 1996/09/01 00:01 [medline] PHST- 1996/09/01 00:00 [entrez] PST - ppublish SO - Arch Mal Coeur Vaiss. 1996 Sep;89(9):1185-7.