Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Circ Res
2019 Feb 15;1244:539-552. doi: 10.1161/CIRCRESAHA.118.314050.
Show Gene links
Show Anatomy links
Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation.
Zhu W
,
Mazzanti A
,
Voelker TL
,
Hou P
,
Moreno JD
,
Angsutararux P
,
Naegle KM
,
Priori SG
,
Silva JR
.
???displayArticle.abstract???
RATIONALE: Mutations in the SCN5A gene, encoding the α subunit of the Nav1.5 channel, cause a life-threatening form of cardiac arrhythmia, long QT syndrome type 3 (LQT3). Mexiletine, which is structurally related to the Na+ channel-blocking anesthetic lidocaine, is used to treat LQT3 patients. However, the patient response is variable, depending on the genetic mutation in SCN5A.
OBJECTIVE: The goal of this study is to understand the molecular basis of patients' variable responses and build a predictive statistical model that can be used to personalize mexiletine treatment based on patient's genetic variant.
METHODS AND RESULTS: We monitored the cardiac Na+ channel voltage-sensing domain (VSD) conformational dynamics simultaneously with other gating properties for the LQT3 variants. To systematically identify the relationship between mexiletine block and channel biophysical properties, we used a system-based statistical modeling approach to connect the multivariate properties to patient phenotype. We found that mexiletine altered the conformation of the Domain III VSD, which is the same VSD that many tested LQT3 mutations affect. Analysis of 15 LQT3 variants showed a strong correlation between the activation of the Domain III-VSD and the strength of the inhibition of the channel by mexiletine. Based on this improved molecular-level understanding, we generated a systems-based model based on a dataset of 32 LQT3 patients, which then successfully predicted the response of 7 out of 8 patients to mexiletine in a blinded, retrospective trial.
CONCLUSIONS: Our results imply that the modulated receptor theory of local anesthetic action, which confines local anesthetic binding effects to the channel pore, should be revised to include drug interaction with the Domain III-VSD. Using an algorithm that incorporates this mode of action, we can predict patient-specific responses to mexiletine, improving therapeutic decision making.
???displayArticle.pubmedLink???
30566038
???displayArticle.pmcLink???PMC6588292 ???displayArticle.link???Circ Res ???displayArticle.grants???[+]
Arcisio-Miranda,
Molecular mechanism of allosteric modification of voltage-dependent sodium channels by local anesthetics.
2010, Pubmed,
Xenbase
Arcisio-Miranda,
Molecular mechanism of allosteric modification of voltage-dependent sodium channels by local anesthetics.
2010,
Pubmed
,
Xenbase
Cocco,
Torsades de pointes as a manifestation of mexiletine toxicity.
1980,
Pubmed
Duff,
Mexiletine-quinidine combination: electrophysiologic correlates of a favorable antiarrhythmic interaction in humans.
1987,
Pubmed
Duff,
Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine.
1983,
Pubmed
Echt,
Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.
1991,
Pubmed
Fitzgerald,
Systems biology and combination therapy in the quest for clinical efficacy.
2006,
Pubmed
Gellens,
Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel.
1992,
Pubmed
,
Xenbase
Hanck,
Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity.
2009,
Pubmed
Hille,
Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.
1977,
Pubmed
Hsu,
Regulation of Na+ channel inactivation by the DIII and DIV voltage-sensing domains.
2017,
Pubmed
,
Xenbase
Janes,
Data-driven modelling of signal-transduction networks.
2006,
Pubmed
Jordaens,
Combination of flecainide and mexiletine for the treatment of ventricular tachyarrhythmias.
1990,
Pubmed
Makielski,
A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels.
2003,
Pubmed
Mangold,
Mechanisms and models of cardiac sodium channel inactivation.
2017,
Pubmed
Mazzanti,
Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3.
2016,
Pubmed
McKeithan,
An Automated Platform for Assessment of Congenital and Drug-Induced Arrhythmia with hiPSC-Derived Cardiomyocytes.
2017,
Pubmed
Muroi,
Molecular determinants of coupling between the domain III voltage sensor and pore of a sodium channel.
2010,
Pubmed
NULL,
International mexiletine and placebo antiarrhythmic coronary trial: I. Report on arrhythmia and other findings. Impact Research Group.
1984,
Pubmed
Peters,
Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation.
2017,
Pubmed
,
Xenbase
Ragsdale,
Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.
1996,
Pubmed
Ragsdale,
Molecular determinants of state-dependent block of Na+ channels by local anesthetics.
1994,
Pubmed
,
Xenbase
Ruan,
Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients.
2007,
Pubmed
Rudokas,
The Xenopus oocyte cut-open vaseline gap voltage-clamp technique with fluorometry.
2014,
Pubmed
,
Xenbase
Schwartz,
Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.
2001,
Pubmed
Sheets,
Molecular action of lidocaine on the voltage sensors of sodium channels.
2003,
Pubmed
Shimizu,
Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome.
2000,
Pubmed
Varga,
Direct Measurement of Cardiac Na+ Channel Conformations Reveals Molecular Pathologies of Inherited Mutations.
2015,
Pubmed
Wang,
Pharmacological targeting of long QT mutant sodium channels.
1997,
Pubmed
Yuan,
Investigations of the Navβ1b sodium channel subunit in human ventricle; functional characterization of the H162P Brugada syndrome mutant.
2014,
Pubmed
Zehender,
Prediction of efficacy and tolerance of oral mexiletine by intravenous lidocaine application.
1988,
Pubmed
Zhu,
Mechanisms of noncovalent β subunit regulation of NaV channel gating.
2017,
Pubmed
Zhu,
Molecular motions that shape the cardiac action potential: Insights from voltage clamp fluorometry.
2016,
Pubmed