@article{91c464db26f54baf88e7986b35726925,
title = "Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: Evidence from bench, bedside, and community",
abstract = "AimsNon-cardiac drugs that impair cardiac repolarization (electrocardiographic QT prolongation) are associated with an increased sudden cardiac arrest (SCA) risk. Emerging evidence suggests that non-cardiac drugs that impair cardiac depolarization and excitability (electrocardiographic QRS prolongation) also increase the risk for SCA. Nortriptyline, which blocks the SCN5A-encoded cardiac sodium channel, may exemplify such drugs. We aimed to study whether nortriptyline increases the risk for SCA, and to establish the underlying mechanisms.Methods and resultsWe studied QRS durations during rest/exercise in an index patient who experienced ventricular tachycardia during exercise while using nortriptyline, and compared them with those of 55 controls with/without nortriptyline and 24 controls with Brugada syndrome (BrS) without nortriptyline, who carried an SCN5A mutation. We performed molecular-genetic (exon-trapping) and functional (patch-clamp) experiments to unravel the mechanisms of QRS prolongation by nortriptyline and the SCN5A mutation found in the index patient. We conducted a prospective community-based study among 944 victims of ECG-documented SCA and 4354-matched controls to determine the risk for SCA associated with nortriptyline use. Multiple mechanisms may act in concert to increase the risk for SCA during nortriptyline use. Pharmacological (nortriptyline), genetic (loss-of-function SCN5A mutation), and/or functional (sodium channel inactivation at fast heart rates) factors conspire to reduce the cardiac sodium current and increase the risk for SCA. Nortriptyline use in the community was associated with a 4.5-fold increase in the risk for SCA [adjusted OR: 4.5 (95% CI: 1.1-19.5)], particularly when other sodium channel-blocking factors were present.ConclusionsNortriptyline increases the risk for SCA in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel.",
keywords = "Electrophysiology, Epidemiology, Ion channels, Nortriptyline, Sudden Death",
author = "Abdennasser Bardai and Amin, {Ahmad S.} and Blom, {Marieke T.} and Bezzina, {Connie R.} and Jocelyn Berdowski and Langendijk, {Pim N.J.} and Leander Beekman and Klemens, {Christine A.} and Souverein, {Patrick C.} and Koster, {Rudolph W.} and {De Boer}, Anthonius and Tan, {Hanno L.}",
note = "Funding Information: The authors greatly appreciate the contributions of Paulien Homma, Steffie Beesems, Michiel Hulleman, Esther Landman, and Renate van der Meer to the data collection, data entry, and patient follow-up at the Academic Medical Center, and are greatly indebted to the dispatch centers, ambulance paramedics, and first responders of Amsterdam en Omstreken, Kennemerland, and Noord-Holland Noord for their cooperation and support. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). This study makes use of data generated by the Genome of the Netherlands Project. A full list of the investigators is available from http://www.dutchgenomeproject.com/. Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated 9 July 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). Funding Information: H.L.T. was supported by the Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616), the Dutch Medicines Evaluation Board (MEB/CBG), the European Community{\textquoteright}s Seventh Framework Programme (FP7, grant 241679, ARITMO), and Biobanking and Biomolecular Research Infrastructure The Netherlands (BBMRI-NL). R.W.K. was supported by Physio Control and the Netherlands Heart Foundation (grant 2006B179). A.B. was supported by the Netherlands Organization for Scientific Research (NWO, grant Mozaiek 017.003.084). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.",
year = "2013",
month = may,
day = "21",
doi = "https://doi.org/10.1093/eurheartj/eht054",
language = "English",
volume = "34",
pages = "1506--1516",
journal = "European Heart journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "20",
}