title: G-CSF therapy reduces myocardial repolarization reserve in the presence of increased arteriogenesis, angiogenesis and connexin 43 expression in an experimental model of pacing-induced heart failure.
abstract: G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10 μg/kg G-CSF s.c. over 17 ± 4 days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33 ± 12 ms; p < 0.01). Moreover, a significant increase in dispersion of repolarization contributed to a significantly higher rate of ventricular tachyarrhythmias in CHF. G-CSF-pre-treated hearts showed a further increase in prolongation of repolarization as compared with S and CHF. The further increase in dispersion of repolarization [S-G-CSF: +23 ± 9 ms (spatial), +13 ± 7 ms (temporal); CHF-G-CSF: +38 ± 14 ms (spatial), +10 ± 4 ms (temporal); p < 0.05 as compared with S and CHF], increased the incidence of ventricular tachyarrhythmias. In summary, chronic G-CSF treatment has moderate beneficial effects on parameters potentially related to hemodynamic function in the non-ischemic rabbit CHF model. However, a significant reduction of repolarization reserve might seriously challenge its suitability as a therapeutic agent for chronic CHF therapy.
authors.affiliation: Division of Clinical and Experimental Electrophysiology, Department of Cardiology and Angiology, Hospital of the Westfälische Wilhelms-University, Münster, Germany. milbergp@uni-muenster.de
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Rainer
authors.initials: R
authors.lastname: Klocke
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.forename: Trong Hung
authors.initials: TH
authors.lastname: Quang
authors.forename: Kati
authors.initials: K
authors.lastname: Dieks
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Michael
authors.initials: M
authors.lastname: Kuhlmann
authors.forename: Michael
authors.initials: M
authors.lastname: Fehr
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
authors.forename: Sigrid
authors.initials: S
authors.lastname: Nikol
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D018031:Connexin 43 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D005455:Fluorescent Antibody Technique; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D011817:Rabbits
chemical_list: D018031:Connexin 43; D016179:Granulocyte Colony-Stimulating Factor