title: Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes.
abstract: Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.
authors.affiliation: Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Münster, Germany. milbergp@uni-muenster.de
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Bruns
authors.forename: Julia
authors.initials: J
authors.lastname: Biertz
authors.forename: Shahram
authors.initials: S
authors.lastname: Ramtin
authors.forename: Nico
authors.initials: N
authors.lastname: Reinsch
authors.forename: Dirk
authors.initials: D
authors.lastname: Fleischer
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haverkamp
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D017963:Azithromycin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D017291:Clarithromycin / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D004917:Erythromycin / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D011817:Rabbits; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D000900:Anti-Bacterial Agents; D004917:Erythromycin; D017963:Azithromycin; D017291:Clarithromycin