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01-11-2011 | Original Contribution

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

Authors: Peter Milberg, Rainer Klocke, Gerrit Frommeyer, Trong Hung Quang, Kati Dieks, Jörg Stypmann, Nani Osada, Michael Kuhlmann, Michael Fehr, Hendrik Milting, Sigrid Nikol, Johannes Waltenberger, Günter Breithardt, Lars Eckardt

Published in: Basic Research in Cardiology | Issue 6/2011

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.

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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
Authors: Peter Milberg
Rainer Klocke
Gerrit Frommeyer
Trong Hung Quang
Kati Dieks
Jörg Stypmann
Nani Osada
Michael Kuhlmann
Michael Fehr
Hendrik Milting
Sigrid Nikol
Johannes Waltenberger
Günter Breithardt
Lars Eckardt
Publication date: 01-11-2011
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 6/2011
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-011-0230-8

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