title: Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community.
abstract: OBJECTIVE
  Non-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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Nortriptyline 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.
authors: Heart Failure Research Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Abdennasser
authors: A
authors: Bardai
authors: Ahmad S
authors: AS
authors: Amin
authors: Marieke T
authors: MT
authors: Blom
authors: Connie R
authors: CR
authors: Bezzina
authors: Jocelyn
authors: J
authors: Berdowski
authors: Pim N J
authors: PN
authors: Langendijk
authors: Leander
authors: L
authors: Beekman
authors: Christine A
authors: CA
authors: Klemens
authors: Patrick C
authors: PC
authors: Souverein
authors: Rudolph W
authors: RW
authors: Koster
authors: Anthonius
authors: A
authors: de Boer
authors: Hanno L
authors: HL
authors: Tan
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D009661:Nortriptyline / Q000009:adverse effects*; D011446:Prospective Studies; D012307:Risk Factors; D062687:Sodium Channel Agonists / Q000009:adverse effects*; D017180:Tachycardia, Ventricular / Q000139:chemically induced
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D062687:Sodium Channel Agonists; D009661:Nortriptyline
keywords: Electrophysiology; Epidemiology; Ion channels; Nortriptyline; Sudden Death