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Review
. 2016 May 1;594(9):2459-68.
doi: 10.1113/JP270526. Epub 2016 Jan 18.

Predicting drug-induced QT prolongation and torsades de pointes

Dan M Roden  1
Affiliations
Review

Predicting drug-induced QT prolongation and torsades de pointes

Dan M Roden. J Physiol. .

Abstract

Drugs used to treat cardiovascular disease as well as those used in the treatment of multiple other conditions can occasionally produce exaggerated prolongation of the QT interval on the electrocardiogram and the morphologically distinctive polymorphic ventricular tachycardia ('torsades de pointes'). This syndrome of drug-induced long QT syndrome has moved from an interesting academic exercise to become a key element in the development of any new drug entity. The prevailing view, which has driven both clinical care and drug regulation, holds that cardiac repolarization represents a balance between inward currents (primarily through calcium and sodium channels) and outward currents (primarily through rapid and slowed delayed rectifier potassium channels) and that block of the rapid delayed rectifier (IKr ) is the primary mechanism whereby drugs prolong individual action potentials, manifest on the surface electrocardiogram as QT interval prolongation. Such marked action potential prolongation in individual cardiac cells, in turn, is accompanied by arrhythmogenic afterdepolarizations thought to trigger torsades de pointes. This review describes the evidence in support of this construct, and describes the way in which clinical and whole heart experiments have informed molecular mechanisms and vice versa. New data that challenge these views and that may, as a result, lead to new clinical care and drug screening paradigms, are discussed.

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Figures

Figure 1
Figure 1. Development of torsades de pointes in a patient with atrial fibrillation treated with sotalol
A, atrial fibrillation. B, with sotalol, the rhythm converts to sinus with a borderline prolonged QT interval (∼480 ms). C, several hours later, the QT interval after sinus beats is markedly prolonged (> 600 ms; red arrows), and single ectopic beats, possibly representing early afterdepolarization‐mediated automaticity (Abstract Figure B) are seen. D, this is followed within minutes by bursts of the polymorphic ventricular tachycardia torsades de pointes, indicated by the dashed lines.
See this image and copyright information in PMC

References

    1. Abraham JM, Saliba WI, Vekstein C, Lawrence D, Bhargava M, Bassiouny M, Janiszewski D, Lindsay BD, Militello M, Nissen SE, Poe S, Tanaka‐Esposito C, Wolski K & Wilkoff BL (2015). Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter. Circ Arrhythm Electrophysiol 8, 772–776. - PubMed
    1. Altin T, Ozcan O, Turhan S, Ongun OA, Akyurek O, Karaoguz R & Guldal M (2007). Torsade de pointes associated with moxifloxacin: a rare but potentially fatal adverse event. Can J Cardiol 23, 907–908. - PMC - PubMed
    1. Antzelevitch C (2007). Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes. Am J Physiol Heart Circ Physiol 293, H2024–H2038. - PMC - PubMed
    1. Antzelevitch C, Burashnikov A, Sicouri S & Belardinelli L (2011). Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm 8, 1281–1290. - PMC - PubMed
    1. Arking DE, Pulit SL, Crotti L, van der Harst P, Munroe PB, Koopmann TT, Sotoodehnia N, Rossin EJ, Morley M, Wang X, Johnson AD, Lundby A, Gudbjartsson DF, Noseworthy PA, Eijgelsheim M, Bradford Y, Tarasov KV, Dorr M, Muller‐Nurasyid M, Lahtinen AM, Nolte IM, Smith AV, Bis JC, Isaacs A, Newhouse SJ, Evans DS, Post WS, Waggott D, Lyytikainen LP, Hicks AA, Eisele L, Ellinghaus D, Hayward C, Navarro P, Ulivi S, Tanaka T, Tester DJ, Chatel S, Gustafsson S, Kumari M, Morris RW, Naluai AT, Padmanabhan S, Kluttig A, Strohmer B, Panayiotou AG, Torres M, Knoflach M, Hubacek JA, Slowikowski K, Raychaudhuri S, Kumar RD, Harris TB, Launer LJ, Shuldiner AR, Alonso A, Bader JS, Ehret G, Huang H, Kao WH, Strait JB, Macfarlane PW, Brown M, Caulfield MJ, Samani NJ, Kronenberg F, Willeit J, Smith JG, Greiser KH, Meyer Zu Schwabedissen H, Werdan K, Carella M, Zelante L, Heckbert SR, Psaty BM, Rotter JI, Kolcic I, Polasek O, Wright AF, Griffin M, Daly MJ, Arnar DO, Holm H, Thorsteinsdottir U, Denny JC, Roden DM, Zuvich RL, Emilsson V, Plump AS, Larson MG, O'Donnell CJ, Yin X, Bobbo M, D'Adamo AP, Iorio A, Sinagra G, Carracedo A, Cummings SR, Nalls MA, Jula A, Kontula KK, Marjamaa A, Oikarinen L, Perola M, Porthan K, Erbel R, Hoffmann P, Jockel KH, Kalsch H, Nothen MM, den Hoed M, Loos RJ, Thelle DS, Gieger C, Meitinger T, Perz S, Peters A, Prucha H, Sinner MF, Waldenberger M, de Boer RA, Franke L, van der Vleuten PA, Beckmann BM, Martens E, Bardai A, Hofman N, Wilde AA, Behr ER, Dalageorgou C, Giudicessi JR, Medeiros‐Domingo A, Barc J, Kyndt F, Probst V, Ghidoni A, Insolia R, Hamilton RM, Scherer SW, Brandimarto J, Margulies K, Moravec CE, Greco MF, Fuchsberger C, O'Connell JR, Lee WK, Watt GC, Campbell H, Wild SH, El Mokhtari NE, Frey N, Asselbergs FW, Mateo Leach I, Navis G, van den Berg MP, van Veldhuisen DJ, Kellis M, Krijthe BP, Franco OH, Hofman A, Kors JA, Uitterlinden AG, Witteman JC, Kedenko L, Lamina C, Oostra BA, Abecasis GR, Lakatta EG, Mulas A, Orru M, Schlessinger D, Uda M, Markus MR, Volker U, Snieder H, Spector TD, Arnlov J, Lind L, Sundstrom J, Syvanen AC, Kivimaki M, Kahonen M, Mononen N, Raitakari OT, Viikari JS, Adamkova V, Kiechl S, Brion M, Nicolaides AN, Paulweber B, Haerting J, Dominiczak AF, Nyberg F, Whincup PH, Hingorani AD, Schott JJ, Bezzina CR, Ingelsson E, Ferrucci L, Gasparini P, Wilson JF, Rudan I, Franke A, Muhleisen TW, Pramstaller PP, Lehtimaki TJ, Paterson AD, Parsa A, Liu Y, van Duijn CM, Siscovick DS, Gudnason V, Jamshidi Y, Salomaa V, Felix SB, Sanna S, Ritchie MD, Stricker BH, Stefansson K, Boyer LA, Cappola TP, Olsen JV, Lage K, Schwartz PJ, Kaab S, Chakravarti A, Ackerman MJ, Pfeufer A, de Bakker PI & Newton‐Cheh C (2014). Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 46, 826–836. - PMC - PubMed

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