Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome

Shimizu, Wataru; Antzelevitch, Charles

doi:10.1161/01.cir.96.6.2038

Cited by 465 publications

(342 citation statements)

References 44 publications

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“…*p<.0005 vs. Control; †p<.0005, † †p<.005, † † †p<.05, vs. 293B, d-sotalol (d-Sot) or ATX-II. Modified from references (Shimizu & Antzelevitch, 1997, 2000a with permission. Although 20 μmol/L mexiletine does not completely reverse the effect of the drug to prolong the QT interval and APD in the LQT1 (A) and LQT2 (B) models, mexiletine was effective in markedly reducing TDR due to a greater abbreviation of the APD of the M cell than that of Epi.…”

Section: Resultsmentioning

confidence: 99%

“…Although 20 μmol/L mexiletine does not completely reverse the effect of the drug to prolong the QT interval and APD in the LQT1 (A) and LQT2 (B) models, mexiletine was effective in markedly reducing TDR due to a greater abbreviation of the APD of the M cell than that of Epi. Modified from references (Shimizu & Antzelevitch, 1997) with permission. …”

Section: Resultsmentioning

confidence: 99%

“…While the benefits of Class IB agents are clearly apparent in experimental models of LQT3, data from studies utilizing the perfused-wedge preparation indicate that mexiletine is also effective in abbreviating the TDR and suppressing TdP in LQT1 and LQT2 models (Fig. 2) (Shimizu & Antzelevitch, 1997. The antiarrhythmic effect of mexiletine is attributed to reduction of TDR in all three models, secondary to preferential abbreviation of APD of M cells which in-trinsically possesses stronger late I Na (Zygmunt et al, 2001).…”

Section: Sodium Channel Blocker-lqt3mentioning

confidence: 95%

“…Experimental preparations in the form of arterially-perfused canine left ventricular wedge preparations have been helpful in delineating the cellular basis of the characteristic phenotypic T wave morphologies as well as genotype-specific response to sympathetic stimuli in LQT1, LQT2 and LQT3 (Shimizu & Antzelevitch, 1997Yan & Antzelevitch, 1998;Antzelevitch et al, 1999;Shimizu & Antzelevitch, 1999a,b, 2000a. In these studies, chromanol 293B (specific I Ks blocker), d-sotalol (specific I Kr blocker) and ATX-II (used to augment late I Na ) were used to create the experimental conditions mimicking LQT1, LQT2 and LQT3, respectively ( Fig.…”

Section: Genotype-phenotype Correlation-experimental Explanationmentioning

confidence: 99%

“…Abbreviation of QT interval with exercise is most pronounced in LQT3 as compared to LQT1 and LQT2 because of the steeper QT-RR relationship (Schwartz et al, 1995;Shimizu & Antzelevitch, 1997. Moreover, LQT3 patients are at highest risk of TdP when heart rate is slow.…”

Section: Pacemaker and Defibrillator Therapy-mentioning

confidence: 99%

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Pharmacological approach to the treatment of long and short QT syndromes

Patel

Antzelevitch

2008

Pharmacology & Therapeutics

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Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available.The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%