Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block
Publication Date
December 30, 2016
Journal
PLOS ONE
Authors
Jose Vicente, Lars Johannesen, Meisam Hosseini, Jay W. Mason, et al
Volume
11
Issue
12
Pages
e0163619
DOI
https://dx.plos.org/10.1371/journal.pone.0163619
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0163619
Scopus
85007580029
Mendeley
http://www.mendeley.com/research/electrocardiographic-biomarkers-detection-druginduced-late-sodium-current-block
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Mendeley | Further Information

{"title"=>"Electrocardiographic biomarkers for detection of drug-induced late sodium current block", "type"=>"journal", "authors"=>[{"first_name"=>"Jose", "last_name"=>"Vicente", "scopus_author_id"=>"57191195296"}, {"first_name"=>"Lars", "last_name"=>"Johannesen", "scopus_author_id"=>"37079221300"}, {"first_name"=>"Meisam", "last_name"=>"Hosseini", "scopus_author_id"=>"57192713459"}, {"first_name"=>"Jay W.", "last_name"=>"Mason", "scopus_author_id"=>"7403552214"}, {"first_name"=>"Philip T.", "last_name"=>"Sager", "scopus_author_id"=>"7005362726"}, {"first_name"=>"Esther", "last_name"=>"Pueyo", "scopus_author_id"=>"7004512193"}, {"first_name"=>"David G.", "last_name"=>"Strauss", "scopus_author_id"=>"36785057800"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"85007580029", "pmid"=>"28036334", "pui"=>"613932146", "isbn"=>"1932-6203", "scopus"=>"2-s2.0-85007580029", "doi"=>"10.1371/journal.pone.0163619", "issn"=>"19326203"}, "id"=>"f0d3a71a-4fee-3cd8-916a-8c6b9c54a7ec", "abstract"=>"BACKGROUND Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the \"CiPA\" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. METHODS AND RESULTS In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). CONCLUSIONS Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block. TRIAL REGISTRATION NCT02308748 and NCT01873950.", "link"=>"http://www.mendeley.com/research/electrocardiographic-biomarkers-detection-druginduced-late-sodium-current-block", "reader_count"=>13, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>1, "Other"=>4, "Student > Master"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>1, "Other"=>4, "Student > Master"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>3, "Medicine and Dentistry"=>5, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "group_count"=>0}

Scopus | Further Information

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