title: Coxsackievirus B3 modulates cardiac ion channels.
abstract: Infections with coxsackieviruses of type B (CVBs), which are known to induce severe forms of acute and chronic myocarditis, are often accompanied by ventricular arrhythmias and sudden cardiac death. The mechanisms underlying the development of virus-induced, life-threatening arrhythmias, which are phenotypically similar to those observed in patients having functionally impaired cardiac ion channels, remain, however, enigmatic. In the present study, we show, for the first time, modulating time-dependent effects of CVB3 on the cardiac ion channels KCNQ1, hERG1, and Cav1.2 in heterologous expression. Channel protein abundance in cellular plasma membrane and patterns of their subcellular distribution were altered in infected murine hearts. The antiviral compound AG7088 did not prevent these effects on channels. In silico analyses of infected human myocytes suggest pronounced alterations of electrical and calcium signaling and increased risk of arrhythmogenesis. These modifications are attenuated by the common Asian polymorphism KCNQ1 P448R, a genetic determinant preventing coxsackievirus-induced effects in vitro. This study provides a previously unknown explanation for the development of arrhythmias in enteroviral myocarditis, which will help to develop therapeutic strategies for arrhythmia treatment.
authors.affiliation: 2Institut für Genetik von Herzerkrankungen (IfGH), Abteilung Myozelluläre Elektrophysiologie, Albert-Schweitzer-Campus 1 (Gebäude D3), D-48149 Münster. guiscard.seebohm@ukmuenster.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Steinke
authors.forename: Frank
authors.initials: F
authors.lastname: Sachse
authors.forename: Nicole
authors.initials: N
authors.lastname: Ettischer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
authors.forename: Ulrike
authors.initials: U
authors.lastname: Henrion
authors.forename: Matthias
authors.initials: M
authors.lastname: Rohrbeck
authors.forename: Rafael
authors.initials: R
authors.lastname: Klosowski
authors.forename: Dirk
authors.initials: D
authors.lastname: Wolters
authors.forename: Stefan
authors.initials: S
authors.lastname: Brunner
authors.forename: Wolfgang-Michael
authors.initials: WM
authors.lastname: Franz
authors.forename: Lutz
authors.initials: L
authors.lastname: Pott
authors.forename: Carlos
authors.initials: C
authors.lastname: Munoz
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
mesh_terms: D000818:Animals; D003198:Computer Simulation; D029822:Enterovirus B, Human / Q000145:classification* / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000821:virology; D009865:Oocytes; D011110:Polymorphism, Genetic; D021381:Protein Transport / Q000502:physiology*; D014981:Xenopus
chemical_list: D007473:Ion Channels
keywords: CVB3; arrhythmias; myocarditis; trafficking