LQT1 Patients Research Articles

Improvement of repolarization abnormalities by a K+ channel opener in the LQT1 form of congenital long-QT syndrome.

This study used monophasic action potential (MAP) to examine the effect of nicorandil, a K+ channel opener, on repolarization abnormalities induced by epinephrine in the LQT1 form of congenital long-QT syndrome in which the KvLQT1 mutation underlies the defect in the channel responsible for the slowly activating component of the delayed rectifier potassium current. MAPs were recorded simultaneously from two or three sites on the right ventricular and left ventricular endocardium in 6 patients with a congenital form of LQT1 syndrome with KvLQT1 defect (17 sites) and 8 control patients (24 sites). In LQT1 patients, epinephrine infusion prolonged the QT interval and 90% MAP duration (MAPD90) and increased the dispersion of MAPD90. Epinephrine also induced early after depolarizations (EADs) as well as ventricular premature complexes (VPCs) in 2 of the 6 patients. Nicorandil during epinephrine infusion abbreviated the QT interval and MAPD90, decreased the dispersion of MAPD90, and abolished the EADs as well as the VPCs in 1 patient. Addition of propranolol completely reversed the effect of epinephrine in prolonging the QT interval and MAPD90 and increasing the dispersion and eliminated the EADs and VPCs in another patient. In control patients, the effect of epinephrine and that of additional nicorandil and propranolol on repolarization parameters were much less than in the LQT1 patients. Our results suggest that nicorandil, a K+ channel opener, improves repolarization abnormalities in the LQT1 form of congenital long-QT syndrome with KvLQT1 defect.

Genetics, molecular mechanisms and management of long QT syndrome

Cardiac arrhythmias cause more than 300 000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome llpl5.5, HERG (LQT2) on chromosome 7q35–36, SCNSA (LQT3) on chromosome 3p21–24, and MinK (LQT5) on chromosome 21q22. SCNSA encodes the cardiac sodium channel, and LQT-causing mutations in SCNSA lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCNSA mutations. HERG encodes the cardiac I potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the IKs potassium channel. Genetic testing is now available for some patients with LQT.

Molecular biology of the long QT syndrome: impact on management.

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.

Differential Response to Na + Channel Blockade, β-Adrenergic Stimulation, and Rapid Pacing in a Cellular Model Mimicking the SCN5A and HERG Defects Present in the Long-QT Syndrome

The long-QT syndrome (LQTS) is a hereditary disorder characterized by an abnormally prolonged QT interval and by life-threatening arrhythmias. Recently, two of the genes responsible for LQTS have been identified: SCN5A, a voltage-dependent Na+ channel on chromosome 3 (LQT3), and HERG, responsible for the rapid component of the delayed rectifier current (IKr), on chromosome 7 (LQT2). We developed an in vitro model to attempt reproduction of the expected alterations in LQT3 and LQT2 patients. Guinea pig ventricular myocytes were exposed to anthopleura toxin A (anthopleurin), an inhibitor of the inactivation of the Na+ current, and to dofetilide, a selective blocker of IKr. Both interventions significantly prolonged action potential duration (APD), by 54 +/- 13 and 62 +/- 16 ms, respectively. Cells pretreated with anthopleurin significantly shortened APD in response to mexiletine, isoproterenol, and rapid pacing (from 264 +/- 38 to 226 +/- 32 ms after mexiletine, P < .001). On the contrary, cells exposed to dofetilide did not shorten the APD after mexiletine and even prolonged it after initial exposure to isoproterenol (from 280 +/- 25 to 313 +/- 20 ms, P < .001); during rapid pacing, APD was shortened but less (38 +/- 9 versus 60 +/- 11 ms, P < .05) than in anthopleurin-treated cells. This study shows that a cellular model for LQTS, based on the recent advances in molecular genetics, can provide adequate "phenotypes" of prolonged repolarization amenable to the testing of interventions of potential clinical relevance. We found differential responses to Na+ channel blockade, to beta-adrenergic stimulation, and to rapid pacing according to specific pretreatment with either anthopleurin (to mimic LQT3) or dofetilide (to mimic LQT2). These different responses in myocytes bear striking similarities with the differential response to analogous interventions in LQTS patients with mutations on the SCN5A and HERG genes.

Long QT Syndrome Patients With Mutations of the SCN5A and HERG Genes Have Differential Responses to Na + Channel Blockade and to Increases in Heart Rate

The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate. Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QTc were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QTc from 535 +/- 32 to 445 +/- 31 ms, P < .005) but not among LQT2 patients (QTc from 530 +/- 79 to 503 +/- 60 ms, P = NS). LQT3 patients (n = 7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n = 4) and also more than 18 healthy control subjects (9.45 +/- 3.3 versus 3.95 +/- 1.97 and 2.83 +/- 1.33, P < .05; data expressed as percent reduction in QT per 100-ms shortening in RR). Among these patients, there is also a trend for LQT2 patients to have syncope or cardiac arrest under emotional or physical stress and for LQT3 patients to have cardiac events either at rest or during sleep. This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefit from Na+ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates. Conversely, LQT2 patients may be 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 when heart rate increases.