Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community. Bardai Abdennasser,Amin Ahmad S,Blom Marieke T,Bezzina Connie R,Berdowski Jocelyn,Langendijk Pim N J,Beekman Leander,Klemens Christine A,Souverein Patrick C,Koster Rudolph W,de Boer Anthonius,Tan Hanno L European heart journal AIMS: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. METHODS AND 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. 10.1093/eurheartj/eht054

Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline. Villatoro-Gómez Kathya,Pacheco-Rojas David O,Moreno-Galindo Eloy G,Navarro-Polanco Ricardo A,Tristani-Firouzi Martin,Gazgalis Dimitris,Cui Meng,Sánchez-Chapula José A,Ferrer Tania Biochemical pharmacology Amitriptyline (AMIT) is a compound widely prescribed for psychiatric and non-psychiatric conditions including depression, migraine, chronic pain, and anorexia. However, AMIT has been associated with risks of cardiac arrhythmia and sudden death since it can induce prolongation of the QT interval on the surface electrocardiogram and torsade de pointes ventricular arrhythmia. These complications have been attributed to the inhibition of the rapid delayed rectifier potassium current (I). The slow delayed rectifier potassium current (I) is the main repolarizing cardiac current when I is compromised and it has an important role in cardiac repolarization at fast heart rates induced by an elevated sympathetic tone. Therefore, we sought to characterize the effects of AMIT on Kv7.1/KCNE1 and homomeric Kv7.1 channels expressed in HEK-293H cells. Homomeric Kv7.1 and Kv7.1/KCNE1 channels were inhibited by AMIT in a concentration-dependent manner with IC50 values of 8.8 ± 2.1 μM and 2.5 ± 0.8 μM, respectively. This effect was voltage-independent for both homomeric Kv7.1 and Kv7.1/KCNE1 channels. Moreover, mutation of residues located on the P-loop and S6 domain along with molecular docking, suggest that T312, I337 and F340 are the most important molecular determinants for AMIT-Kv7.1 channel interaction. Our experimental findings and modeling suggest that AMIT preferentially blocks the open state of Kv7.1/KCNE1 channels by interacting with specific residues that were previously reported to be important for binding of other compounds, such as chromanol 293B and the benzodiazepine L7. 10.1016/j.bcp.2018.03.016

Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects. Current problems in cardiology Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome first described as a new clinical entity in 1992. Electrocardiographically characterized by distinct coved type ST segment elevation in the right-precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young adults, and less frequently in infants and children. The electrocardiographic manifestations of BrS are often concealed and may be unmasked or aggravated by sodium channel blockers, a febrile state, vagotonic agents, as well as by tricyclic and tetracyclic antidepressants. An implantable cardioverter defibrillator is the most widely accepted approach to therapy. Pharmacologic therapy is designed to produce an inward shift in the balance of currents active during the early phases of the right ventricular action potential (AP) and can be used to abort electrical storms or as an adjunct or alternative to device therapy when use of an implantable cardioverter defibrillator is not possible. Isoproterenol, cilostazol, and milrinone boost calcium channel current and drugs like quinidine, bepridil, and the Chinese herb extract Wenxin Keli inhibit the transient outward current, acting to diminish the AP notch and thus to suppress the substrate and trigger for ventricular tachycardia or fibrillation. Radiofrequency ablation of the right ventricular outflow tract epicardium of patients with BrS has recently been shown to reduce arrhythmia vulnerability and the electrocardiographic manifestation of the disease, presumably by destroying the cells with more prominent AP notch. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of BrS as well as the approach to therapy. 10.1016/j.cpcardiol.2015.06.002