title: Reduced repolarization reserve due to anthracycline therapy facilitates torsade de pointes induced by IKr blockers.
abstract: BACKGROUND
  Cytostatic agents such as anthracyclines may cause changes in the electrophysiologic properties of the heart. We hypothesized that anthracyclines facilitate life-threatening proarrhythmic side effects of cardiovascular and non-cardiovascular repolarization prolonging drugs.
  
  
  RESULTS
  The electrophysiologic effects of chronic administration of doxorubicin (Dox) were studied in ten rabbits, which were treated with Dox twice a week (1.5 mg/kg i.v.). A control group (11 rabbits) was given NaCl solution. Two of ten Dox rabbits died suddenly, the remaining animals showed mild clinical signs of heart failure after a period of six weeks. Echocardiography demonstrated a decrease in ejection fraction (pre treatment: 74 +/- 23% to post treatment: 63 +/- 16% (p <0.05)). In isolated hearts, action potential duration measured by eight simultaneously recorded monophasic action potentials (MAP) was similar in Dox and control hearts. However, in Dox rabbits, administration of the I(Kr)-blocker erythromycin (150-300 microM) led to a significant greater prolongation of the mean MAP duration (63 +/- 21ms vs 29 +/- 12 ms, p <0.05) and the QT interval (100 +/- 32ms vs 58 +/- 17 ms, p <0.05) as compared to control. Moreover, I(Kr)-block led to a more marked increase of dispersion of MAP(90) in the Dox group as compared to control hearts (23 +/- 7ms vs. 9 +/- 4 ms). In the presence of hypokalemia more episodes of early afterdepolarizations and torsade de pointes occurred (p <0.05).
  
  
  CONCLUSIONS
  Even during the early phase of chemotherapeutic treatment,before significant QT-prolongation is present,anthracyclines lead to an increased sensitivity to the proarrhythmic potency of I(Kr)-blocking drugs. Thus, anthracycline therapy reduces repolarization reserve and thereby represents a novel contributing factor for the development of life-threatening proarrhythmia.
authors.affiliation: Hospital of the Westfälische Wilhelms-University, Dept. of Cardiology and Angiology, Münster, Germany. milbergp@uni-muenster.de
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Dirk
authors.initials: D
authors.lastname: Fleischer
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Gerold
authors.initials: G
authors.lastname: Mönnig
authors.forename: Markus A
authors.initials: MA
authors.lastname: Engelen
authors.forename: Christian
authors.initials: C
authors.lastname: Bruch
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haverkamp
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D004562:Electrocardiography; D004917:Erythromycin / Q000009:adverse effects*; D006329:Heart Conduction System / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D013318:Stroke Volume / Q000187:drug effects; D016171:Torsades de Pointes / Q000139:chemically induced*
chemical_list: D000903:Antibiotics, Antineoplastic; D051668:Delayed Rectifier Potassium Channels; D004917:Erythromycin; D004317:Doxorubicin