Bone marrow-derived stem cells attenuate impaired contractility and enhance capillary density in a rabbit model of Doxorubicin-induced failing hearts.
BACKGROUND
There is a regenerative potential of bone marrow-derived stem cells (BMCs) in ischemic cardiomyopathy, but little is known of their effects in nonischemic cardiomyopathy. This study evaluates the effects of BMC transplantation on contractility and remote capillary density of doxorubicin-induced failing hearts.


METHODS
Heart failure was induced in rabbits by doxorubicin (3 mg/kg; 6 weeks), followed by BMC transplantation (BMC group, 1.5-2.0 x 10(6) cells, n = 15), sham treatment (Medium group, n = 10), or no therapy (Dox group, n = 6). Healthy rabbits were used as controls (n = 10). Cells were transplanted locally into the left ventricle (LV). Four weeks later, contractility was assessed. Cross-sections of hearts were investigated by H&E, Picrosirius red stain, and immunohistologically (Troponin I, alpha-Actinin, Connexin43). Capillary density (CD31-antigen) was examined in the LV, septum, and right ventricle (RV).


RESULTS
Global contractility was significantly higher in the BMC group versus Medium group (ejection fraction: 39.0 +/- 1.4% vs. 30.0 +/- 1.9%, p = 0.002, and fractional shortening: 22 +/- 0.8 vs. 19 +/- 0.6, p < 0.01). Hemodynamic measurements by Millar catheter (Millar Instruments, Houston, TX, USA) were also significantly improved. Capillary density increased in cell-treated hearts (LV: 55 +/- 2.2 vs. 42 +/- 2.0, p < 0.001, RV: 40 +/- 2.1 vs. 35 +/- 1.7, p = 0.065, and septum: 46 +/- 1.5 vs. 39 +/- 1.7, p = 0.005), when compared to the Medium group. The transplanted cells failed to express cardiac markers. The collagen content was reduced in BMC-treated rabbits.


CONCLUSIONS
Despite local cell transplantation, autologous BMCs improve global contractility and enhance remote capillary density and collagen content in doxorubicin-induced cardiomyopathy. However, BMCs failed to transdifferentiate into new cardiomyocytes.
Garbade
Jens
J
Department of Cardiac Surgery, Heart Center Leipzig, University of Leipzig, Leipzig, Germany. garbade@med.uni-leipzig.de
Dhein
Stefan
S
Lipinski
Catherin
C
Aupperle
Heike
H
Arsalan
Mani
M
Borger
Michael A
MA
Barten
Markus J
MJ
Lehmann
Sven
S
Walther
Thomas
T
Mohr
Friedrich-Wilhelm
FW
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001853:Bone Marrow; D016026:Bone Marrow Transplantation; D002196:Capillaries; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000628:therapy*; D006439:Hemodynamics; D008297:Male; D011817:Rabbits; D014463:Ultrasonography
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin