The beneficial effects of postinfarct cytokine combination therapy are sustained during long-term follow-up.
We have previously reported that administration of granulocyte colony-stimulating factor (G-CSF)+Flt-3 ligand (FL) or G-CSF+stem cell factor (SCF) improves left ventricular (LV) function and halts LV remodeling at 35 d after myocardial infarction (MI). In the current study, we investigated whether these beneficial effects are sustained in the long term - an issue of fundamental importance for clinical translation. Mice undergoing a 30-min coronary occlusion followed by reperfusion received vehicle (group I), G-CSF+FL (group II), G-CSF+SCF (group III), or G-CSF alone (group IV) starting 4 h after reperfusion and were euthanized 48 wk later. LV structure and function were assessed by serial echocardiography before and at 48 h and 4, 8, 16, 32, and 48 wk after MI. During follow-up, mice in group I exhibited worsening of LV function and progressive LV remodeling. Compared with group I, both groups II and III exhibited improved LV EF at 4 wk after MI; however, only in group II was this improvement sustained at 48 wk. Group II was also the only group in which the decrease in infarct wall thickening fraction, the LV dilatation, and the increase in LV mass were attenuated vs. group I. We conclude that the beneficial effect of G-CSF+FL on postinfarction LV dysfunction and remodeling is sustained for at least 11 months, and thus is likely to be permanent. In contrast, the effect of G-CSF+SCF was not sustained beyond the first few weeks, and G-CSF alone is ineffective. To our knowledge, this is the first long-term study of cytokines in postinfarction LV remodeling. The results reveal heretofore unknown differential actions of cytokines and have important translational implications.
Sanganalmath
Santosh K
SK
Institute of Molecular Cardiology, University of Louisville, Division of Cardiovascular Medicine, 550 S. Jackson St., ACB, 3rd Floor, Louisville, KY 40292, USA.
Stein
Adam B
AB
Guo
Yiru
Y
Tiwari
Sumit
S
Hunt
Greg
G
Vincent
Robert J
RJ
Huang
Yiming
Y
Rezazadeh
Arash
A
Ildstad
Suzanne T
ST
Dawn
Buddhadeb
B
Bolli
Roberto
R
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology; D016207:Cytokines / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D019089:Stem Cell Factor / Q000494:pharmacology / Q000627:therapeutic use; D013599:Systole / Q000187:drug effects; D013997:Time Factors; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects
D016207:Cytokines; D008565:Membrane Proteins; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor